Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13]2)=[O:8].C1(C)C=CC(S(O[CH2:34][C@@H:35]2[O:37][CH2:36]2)(=O)=O)=CC=1.O>CN(C)C=O>[O:37]1[CH2:36][C@@H:35]1[CH2:34][O:18][C:17]1[C:9]([CH:7]=[O:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCOC(=O)c1cc2c(C=O)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(C=O)c(OC[C@H]3CO3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
Potassium carbonate (0.89 g) was added under nitrogen to a stirred solution of ethyl 4-formyl-5-hydroxyindole-2-carboxylate (1.50 g) in dry dimethylformamide (40 ml). A solution of (R)-glycidyl 4-toluenesulphonate (1.47 g) in dry dimethylformamide (30 ml) was then added and the mixture stirred at ambient temperature for 10 minutes, then at 60° C. for 3 hours. The mixture was poured into water (400 ml) and extracted with ethyl acetate (3×200 ml). The combined extracts were washed with brine (6×200 ml), dried over magnesium sulphate and the solvent evaporated under reduced pressure. The brown solid residue was purified by flash column chromatography on silica eluting with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate to give ethyl (R)-5-(2,3-epoxypropoxy)-4-formylindole-2-carboxylate (1.07 g) as an off-white solid; m.p. 152-154° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([CH:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([Br:13])[CH:15]=2)[C:20]1=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1c2ccc(Br)cc2CCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under dry N2, diisopropylamine (1.7 ml, 0.012 mol) was dissolved in tetrahydrofuran (20 ml) and cooled to -78° C. Butyl lithium (6.88 ml of 1.6 M in hexane, 0.011 mol) was added, and the mixture stirred at -20° C for 0.5 hour and then recooled to -78° C. 6-Bromo-3,4-dihydro-1(2H)-naphthalenone (2.25 g, 0.010 mol; J. Am. Chem. Soc. v. 102, p. 7920, 1980), dissolved in tetrahydrofuran (10 ml) was added, the mixture warmed to -20° C. over 0.5 hour and stirred at that temperature for 15 minutes. Finally benzyl bromide (1.3 ml, 0.011 mol) was added, the mixture warmed over 1 hour to ambient temperature, and stirred at that temperature for 16 hours. The reaction was quenched with two volumes of 10% HCl and extracted with 150 ml ether. The organic layer was washed with 100 ml saturated brine, dried (MgSO4), stripped in vacuo, and the residue chromatographed on silica gel using 1:1 hexane:CH2Cl2 as eluant, monitoring by tlc (1:2 hexane:CH2CL2). Recovered was 380 mg of bis-benzylated product (Rf 0.58), 750 mg of title product (Rf 0.50) and 1.1 g of starting material (Rf 0.28), suitable for recycling.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C@H:5]1[CH2:6][C:7](=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[C:1](=[O:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CC(=O)N1c2ccccc2C(=O)C[C@@H]1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2C(=Nc2ccccc2)C[C@@H]1C

Procedure:
A solution of (2S)-1-acetyl-2-methyl-2,3-dihydro-4(1H)-quinolinone (20 mg, 0.098 mmol; preparation see Tetrahedron: Asymmetry (1998), 9(7), 1137–1142), aniline (36 μl, 0.394 mmol) and a catalytic amount of p-toluene sulfonic acid monohydrate was refluxed overnight in toluene (4 ml) containing molcular sieve 3 Å (0.9 g). The resulting mixture was filtered, concentrated and purified on silica (ethyl acetate:heptane 1:2) to obtain the sub-titled product (22.8 mg, 0.082 mmol).
Reaction SMILES: [NH2:1][CH:2]1[NH:7][CH2:6][CH:5]=[CH:4][NH:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]=[C:17]=[O:18]>CN(C=O)C.O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([NH:1][C:2]1[NH:3][CH2:4][CH2:5][CH2:6][N:7]=1)=[O:18]
Reactant: NC1NC=CCN1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=NCCCN1)Nc1c(Cl)cccc1Cl

Procedure:
A solution of 4.20 g (0.0424 mol) of 2-aminotetrahydropyrimidine in 30 ml of dry DMF was warmed to 70° C. and with stirring was added 7.16 g (0.0381 mol) of 2,6-dichlorophenyl isocyanate in 25 ml of dry DMF over a period of 0.5 hours. After stirring for 2 hours at 70° C., the reaction mixture was cooled, diluted with H2O and filtered. The filter cake was washed well with H2O and air dried. The crude product, 5.1 g (47%) was dissolved in CH2Cl2, dried over K2CO3, filtered through a prewashed pad of filter aid and hexane was added to the cloud point. The resulting crystals were filtered, washed with hexane and dried in vacuo for 3 hours (50° C.; 5 mm Hg) to give pure N-(2,6-dichlorophenyl)-N'-(1,4,5,6-tetrahydropyrimidin-2-yl)urea, 4.71 g (43%); m.p. 179°-180.5° C. TLC: 5×20 cm silica gel; toluene-ether-MeOH (8:4:1) or CHCl3 -MeOH-NH4OH (90:10:1) indicated homogeneity; IR (KBr) 3421,1628 cm-1 ; UV max. (MeOH) 222 nm (ε=28300) and 239 nm (inflection) (ε=18,000).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][N:29]([CH3:37])[CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:33]([CH2:32][CH2:31][CH2:30][N:29]([CH3:37])[CH3:28])(=[O:35])=[O:34])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Reactant: CN(C)CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2c(NC3CCN(S(=O)(=O)CCCN(C)C)CC3)cc(N(C)Cc3ccccc3)nn12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol; purity 80%) was slurred up in 0.3 ml DMA. 3-Dimethylamino-propane-1-sulfonyl chloride Hydrochlorid (0.03 g; 0.14 mmol) and DIPEA (0.06 ml; 0.34 mmol) were added and stirred at 50° C. for 16 hours. Another portion of 3-Dimethylamino-propane-1-sulfonyl chloride Hydrochlorid (0.03 g; 0.14 mmol) and DIPEA (0.06 ml; 0.34 mmol) were added and stirred at 50° C. for additional 16 hours. The crude material was purified by using reversed phase chromatography under acid conditions.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11](Cl)=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)([CH3:26])[CH3:25])=[CH:20][CH:19]=1.C1C[O:37]CC1>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11]([OH:17])=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[CH2:1]([C:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH:8]2[C:11]([OH:37])=[O:12])[C:5]=1[CH2:14][CH:15]=[CH2:16])[CH:2]=[CH2:3].[OH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)([CH3:26])[CH3:25])=[CH:22][CH:23]=1
Reactant: C=CCC1=C(CC=C)C2CC1CC2C(=O)Cl
Reactant: C1CCOC1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Product: C=CCC1=C(CC=C)C2CC1CC2C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
130 g of diallyl-bicyclo[2.2.1]hept-5-ene-2-carbonyl chloride are added dropwise at 20° C. within 30 minutes to a solution of 62.7 g of bisphenol A in 200 ml of pyridine. The mixture is then stirred for 1 hour at 80° C. and then worked up as described in Example 2. This gives 162 g (95% of theory) of a brown, liquid resin with η25 =3,165 mPas. By gel permeation chromatography (THF), the molecular weight is found to be 610 (Mn) or 691 (Mw).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:23][C:17]1[CH:22]=[CH:21][C:20]([C:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:4][CH:3]=2)=[O:11])=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccc(C(=O)c3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 40 g of terephthaloyl chloride and 200 ml of toluene was added in portions 56 g of solid aluminium chloride at such a rate to maintain the reaction temperature at 45°-55°. The thick orange slurry was then heated to 75° for 2 hours, cooled in ice and slowly treated with 200 ml of dilute HCL. The slurry was stirred for 2 hours at room temperature. The solid was collected by filtration, washed with 200 ml of petroleum ether and 2 L of hot water, and dried to constant weight to give 51 g of colorless product, m.p. 178°-187°. This material was used without further purification.
Reaction SMILES: C(O[CH:4]=[C:5]([CH3:12])[C:6](=O)[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][C:5]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:14][NH:15][CH:4]=1
Reactant: CCOC=C(C)C(=O)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1c[nH]nc1C(F)(F)F
Yield: 84.9 %

Procedure:
1.7 g (10.2 mmol) of 4-ethoxy-3-methyl-1,1,1-trifluoro-3-buten-2-on and 0.6 g (12.0 mmol) hydrazine hydrate were stirred in 50 ml of ethanol at room temperature for 2 hours. The ethanol was distilled off under reduced pressure, and the residue was separated with ethyl acetate and water. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.3 g of 4-methyl-3-trifluoromethylpyrazol (yield 86.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12](Cl)=[CH:13][C:14]=1[Cl:15].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>CN(C)C=O.O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:13][C:14]=1[Cl:15]
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Fc1cccc(Cl)c1-c1c(Cl)cc(-c2ccccn2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.8 g (0.26 mol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine (see Example Ab), 83.6 g (0.29 mol) 2-tri-n-butylstannylpyridine and 4.8 g (5.2 mmol) tetrakistriphenylphosphinepalladium(0), dissolved in 600 ml of dimethylformamide and 400 ml 1,4-dioxane, were boiled under reflux for 8 h and then stirred at room temperature overnight. The volatile components were removed under reduced pressure, and 400 ml of water were then added, the mixture was extracted five times with in each case 150 ml of methyl tert-butyl ether and the combined extracts were washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel using cyclohexane/ethyl acetate and triturated with n-pentane. Yield 36.0 g of a colorless solid of m.p. 45° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>CN(C=O)C>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:13][CH2:12][C@H:11]([C:14]([OH:16])=[O:15])[NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 1.84 g (0.0768M) of sodium hydride (NaH) in 50 mL of DMF at 0° C. under a nitrogen atmosphere was added dropwise a slurry of 7.39 g (0.0360M) of N-t-butoxycarbonyl-D-serine. After addition was complete, the reaction was warmed to room temperature and stirred for 45 minutes. The reaction was cooled to -5° C. and 4.04 mL (0.0384M) of 2-fluoronitrobenzene was added dropwise. The reaction was then warmed to room temperature and stirred for 1 hour. The reaction was quenched with an equal volume of water and extracted with ethyl acetate. The ethyl acetate extracts were reextracted with water (pH=9). The water layer was then adjusted to pH=7 and extracted with ethyl acetate. The water layer was then adjusted to pH=2 and extracted with ethyl acetate. The pH=2 ethyl acetate extracts were combined, dried, and evaporated to yield 8.98 g of product as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:7]2[CH:8]=[C:9]([C:12]3[S:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=3[CH3:19])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:7]2[CH:8]=[C:9]([C:12]3[S:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=3[CH3:19])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:31])[O:3]1
Reactant: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Temperature: 25 °C
Yield: 51.6 %

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-4-methylthiophene-2-carbonitrile (5 g, 16.7 mmol) in anhydrous toluene was added, at room temperature under a blanket of nitrogen, Lawesson's reagent (6 g, 14.8 mmol). The reaction mixture was heated at reflux for 2 hrs, allowed to cool to room temperature, and solvent was removed in vacuo. The residue was purified by a silica gel column chromatography (THF:hexane/1:3) to yield the title compound as a yellowish solid (2.4 g, 46%): mp 211–212° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 7.88 (s, 1H), 7.46–7.52 (m, 2H), 7.16 (d, 1H, J=8.3 Hz), 2.30 (s, 3H), 1.68 (s, 6H); MS (ESI) m/z 313 [M−H]−; Anal. Calc. For C16H14N2OS2; C, 61.12; H, 4.49; N, 8.91. Found: C, 60.91; H, 4.48; N, 8.66.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.[I-].[K+].[CH3:33][NH2:34].O>C(O)C>[CH3:33][NH:34][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1
Reactant: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Reactant: CN
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CNCc1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78a) (125 mg) and potassium iodide (5 mg) in a 8M solution of methylamine in ethanol (1.5 mL) was stirred at 20° C. for 16 h. H2O (20 mL) was added and the precipitated collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) the pH of the mixture being set to 11 by addition of 1N NaOH solution, and the solid was isolated by filtration to give the title compound (54 mg) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].CCO[C:13]([S-])=[S:14].[K+]>C(O)C.O>[F:8][C:4]1[C:3]2[N:9]=[C:13]([SH:14])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cccc(F)c1N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1cccc2[nH]c(S)nc12

Procedure:
1,2-diamino-3-fluorobenzene (1.6 g, 12.7 mmol) and potassium ethyl xanthogenate (2.64 g, 16.5 mmol) were dissolved in ethanol (25 ml) and water (6 ml). The mixture was refluxed for 14 hours and then concentrated on a rotavapor. Water (20 ml) was added and the solution was acidified with 2M hydrochloric acid. The precipitate was filtered off and dried. In this way the title compound was obtained (1.23 g, 58%). NMR is given below.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=[O:23].[NH4+].[Cl-]>C1COCC1.O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]([OH:23])[CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccc(CCCBr)cc1OC
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCCC(O)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 0 °C

Procedure:
Under N2, Mg powder (21.15 g, 0.87 gram-atom) was added to a 5 1, 3-neck flask fitted with a mechanical stirrer, condenser, and septum inlet. The Mg was covered with dry THF (200 cc), stirring was begun and a trace of iodine was added followed by about 20 cc then dropwise addition of a solution of 1-bromo,3-(3,4-dimethoxyphenyl)propane (222 g, 0.857 mole) from which all traces of water had been removed in dry THF (1150 cc) at a rate to maintain gentle reflux over a period of 2.5 hours. The resulting dark grey solution was stirred and refluxed for 45 minutes and then cooled to 0° C. With stirring a solution of dried 3,4-dimethoxybenzaldehyde (149.5 g, 0.899 mole) in dry THF (150 cc) was added dropwise over 1 hour at 0° C.-3° C. The resulting mixture was stirred overnight at room temperature, cooled to 0° C., and treated over 1/2 hour at 0°-5° C. with saturated NH4Cl solution (100 cc). The nitrogen atmosphere was discontinued at this point. After standing at room temperature for several hours, the mixture was filtered and the solids were air-dried overnight. The filtrate was evaporated in vacuo to a syrup. The solids were extracted with CH2Cl2 (500 cc) by stirring for a few hours and filtering. The filtrate was combined with the syrup from above and the mixture was diluted with CH2Cl2 (1:1) The organic solution was washed with H2O (3 ×500 cc), dried (Na ), and evaporated in vacuo to a light orange syrup; yield: 300 g (>100%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6](N)[CH2:5][CH2:4]1.O=[C:16]([CH2:20][CH2:21]C(O)=O)[C:17]([OH:19])=[O:18]>C(O)(=O)C>[CH3:2][C:3]1([CH3:14])[C:12]2[C:7]3=[C:8]([C:20]([CH2:16][C:17]([OH:19])=[O:18])=[CH:21][N:6]3[CH2:5][CH2:4]1)[CH:9]=[CH:10][CH:11]=2
Reactant: CC1(C)CCN(N)c2ccccc21
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CC1(C)CCn2cc(CC(=O)O)c3cccc1c32
Yield: 33.9 %

Procedure:
To a solution of glacial acetic acid (80 mL) and concentrated hydrochloric acid (9 mL) was added 3,4-dihydro-4,4-dimethyl-1-(2H)-quinolinamine (9.5 g, 53.9 mmol) and 2-ketoglutaric acid (9.7 g, 65.1 mmol) and the suspension heated at reflux for 3 hours. After cooling the solvents were removed under reduced pressure and the residue dissolved in 500 mL of ethyl acetate. The ethyl acetate solution was washed with water (3×150 mL) and saturated aqueous sodium chloride (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1-4% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 4.45 g (34%) of the desired compound as a tan foam. An impure fraction was extracted with 1N sodium hydroxice (2×50 mL) and the combined aqueous layers washed with diethyl ether (20 mL) and made acidic with concentrated hydrochloric acid (8 mL). This aqueous mixture was extracted with dichloromethane (2×100 mL), followed by drying (Na2SO4) to provide an additional 2.55 g (19%) of desired product
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=2[O:25][CH3:26])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].Cl.O>C(O)C.[Fe]>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:11])[C:2]([OH:1])([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=1[O:25][CH3:26])[C:3]2=[O:15]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2cccc(N)c2C1=O
Yield: 70.3 %

Procedure:
2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (52 mg, 1.4 mmol) was completely dissolved in anhydrous ethanol (10 ml). This solution was added with iron (0.59 g, 10.6 mmol), conc. HCl (0.01 ml) and water (1 ml). The reaction mixture was heated for 3 hrs under reflux. After filtration at high temperature to remove iron, the filtrate was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.32 g, 68%).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([C:36]([OH:38])=O)=[CH:31][CH:30]=2.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[Cl:25][C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([C:36]([NH:2][CH3:1])=[O:38])=[CH:31][CH:30]=2
Reactant: O=C(O)c1ccc2cnc(Cl)cc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2cnc(Cl)cc2c1
Reaction time: 18 h
Yield: 60.4 %

Procedure:
HATU (17.6 mg, 0.046 mmol) was added to a solution of 3-chloroisoquinoline-6-carboxylic acid (Preparation 54, 8 mg, 0.039 mmol), DIPEA (54 uL, 0.31 mmol) and methanamine hydrochloride (15.6 mg, 0.231 mmol) in DMF (4 mL) and the reaction was stirred for 18 hours. The reaction was partitioned between EtOAc and brine, the separated organic phase was washed with saturated NaHCO3 solution, citric acid and brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as yellow oil (5.2 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:17][CH3:16])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccccc2Cl)C1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccccc2Cl)C1
Reaction time: 16 h

Procedure:
A stirred solution of 4.5 g (0.018 mol) of 3-(2-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mol) of 40% aqueous monomethylamine and stirred for 16 h. The reaction mixture was diluted with 200 ml of water and the precipitated product collected by filtration (4.3 g). The crude product was recrystallized from benzene/ligroin yielding 3.9 g (90.0%) of fine white crystals, mp 129.5°-131.5° C.