Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:14]([NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.875 g.) was acetylated with acetic anhydride (7 ml.) and acetic acid (7 ml.) and the acetylation product was recrystallized from ethanol. By the above procedure there was obtained 5-acetylaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as yellow prisms melting at 211°-212° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][OH:31])[CH2:26][NH:27][CH3:28])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[Cl:17][C:18]1[CH:19]=[C:20]([C@H:25]([CH2:29][CH2:30][OH:31])[CH2:26][N:27]([CH3:28])[C:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:15])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2ccccc12
Reactant: CNC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Product: CN(C[C@@H](CCO)c1ccc(Cl)c(Cl)c1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12

Procedure:
By the method of Example 3f, 3-nitro-1-naphthoyl chloride was reacted with (S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl-N-methylamine to give N-[(S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-nitro-1-naphthamide. This was reacted by the method of Example 3g to give the title compound: 1H NMR (300 MHz, CDCl3) δ 9.65 (s), 9.44 (s), 9.07-9.02 (m), 8.38-6.04 (m), 4.44-1.18 (m); MS APCI, m/z=445 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH:8]([C:10]([O:12][CH3:13])=[O:11])[O:9][C:4]=2[C:3]=1[CH2:16][CH2:17][CH3:18].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(OCC)(=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH:8]([C:10]([O:12][CH3:13])=[O:11])[O:9][C:4]=2[C:3]=1[CH2:16][CH2:17][CH3:18]
Reactant: ClCCCBr
Reactant: CCCc1c(O)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCl)ccc2c1OC(C(=O)OC)CC2
Reaction time: 8 h

Procedure:
Methyl 3,4-dihydro-7-hydroxy-8-propyl-2H-1-benzopyran-2-carboxylate (10 g, 40 mmol), 1-bromo-3-chloropropane (75 g, 48 mmol), and potassium carbonate (828 g, 60 mmol) were added to 100 ml of methyl ethyl ketone, and the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, concentrated, and the crude product was chromatographed on silica gel using 20% ethyl acetate/80% hexane as eluant to give the product.
Reaction SMILES: [N+](C1C=CC(C[C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:34])[C:13]3(C(OC(=O)C)C3C=CC4N5C=CN=C5SC=4C=3)Br)[C:10]=2[C:35]([O-:37])=[O:36])=CC=1)([O-])=O.C(#N)C.P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[O:34]=[C:12]1[N:11]2[CH:14]([S:15][CH:9]=[C:10]2[C:35]([OH:37])=[O:36])[CH2:13]1
Reactant: CC(=O)OC(c1ccc2c(c1)sc1nccn12)C1(Br)C(=O)N2C(C(=O)[O-])=C(Cc3ccc([N+](=O)[O-])cc3)SC21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C1=CSC2CC(=O)N12
Temperature: 3 °C

Procedure:
4-Nitrobenzyl-6-[(acetyloxy) (imidazo[2,1-b][1,3]benzothiazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (900 mg, 1.4 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and 0.5 M phosphate buffer (pH 6.5, 20 mL) and hydrogenated over Pd/C (10%) at 40 psi pressure for 6 hrs. The reaction vessel was covered with foil to exclude light. The reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was concentarted and the aqueous layer was washed with ethyl acetate. The aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 180 mg, 36%; as yellow crystals; mp 235° C.; (M+H+Na) 378.
Reaction SMILES: Cl.NO.C([N:7](C(C)C)CC)(C)C.C(O)C.[Cl:16][C:17]1[N:22]=[C:21]([NH:23][C:24]([NH:26]C(OCC)=O)=S)[C:20]([O:32][CH3:33])=[CH:19][CH:18]=1>O>[NH2:7][C:24]1[N:23]=[C:21]2[C:20]([O:32][CH3:33])=[CH:19][CH:18]=[C:17]([Cl:16])[N:22]2[N:26]=1
Reactant: CCOC(=O)NC(=S)Nc1nc(Cl)ccc1OC
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)n2nc(N)nc12
Yield: 58.6 %

Procedure:
Hydroxylamine hydrochloride (9.6 g, 138 mmol) and diisopropylethylamine (14.4 mL, 10.7 g, 83 mmol) were mixed with ethanol (300 mL) for a few minutes and then N-(6-chloro-3-methoxy-2-pyridinyl)-N'-carboethoxythiourea (7.6 g, 27.5 mmol) was added with stirring. The resulting mixture was stirred at room temperature for 20 min and then heated to reflux for 3 hours. The volatile components were removed by evaporation and the residue obtained was mixed with water. The resulting slurry was filtered and the solids collected were washed with ether, a small amount of methanol, and finally hexane and were then dried. The title compound (3.2 g) was obtained as a tan powder melting at 207°-208° C.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[CH3:5][O:6][C:7]1[C:8]([OH:22])=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[C:8]([O:22][CH:2]([CH3:4])[CH3:3])=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CC(C)I
Reactant: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OC(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
2-Iodopropane (0.5 ml, 0.005 mol) was added to a suspension of methyl 3,4-dimethoxy-2-hydroxy-6-nitrobenzoate (1 g, 0.0039 mol) and sodium carbonate (1.6 g, 0.015 mol) in dimethylformamide (15 ml) and the reaction stirred at 60° C. for 2 hours. On cooling, the reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was further extracted with ethyl acetate (2×25 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a crystalline solid (1.1 g, 74%). 1H-NMR (CDCl3): Γ=1.28 (6H, d), 3.94 (9H, m), 4.72 (1H, m), 7.49 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].CS([C:42]1[N:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][N:43]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:42]3[N:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][N:43]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(Oc4ncc(C(F)(F)F)cn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-methane-sulfonyl-5-trifluoromethyl-pyrimidine
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].[C:20]([C:26]([O:28][CH3:29])=[O:27])#[C:21][C:22]([O:24][CH3:25])=[O:23].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])/[C:21](/[CH:11]([P:6]([O:8][CH2:9][CH3:10])([O:5][CH2:3][CH3:4])=[O:7])[P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])=[CH:20]\[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(/C(=C/C(=O)OC)C(=O)OC)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
In a suspension of 1.33 g of sodium hydride (60% in oil) in 120 ml of toluene are added dropwise 10 g of bis(diethoxyphosphoryl)methane dissolved in 20 ml of toluene. The reaction mixture is kept at room temperature under stirring for 1 hour, then it is cooled to 0° C. and added dropwise with a solution of dimethyl acetylenedicarboxylate (5.17 g) in 20 ml of toluene. After 1 hour under stirring the reaction mixture is added with ethyl acetate until dissolution of the formed gummy solid occurs and it is washed firstly with 1 N hydrochloric acid (30 ml) then with water (2×30 ml). The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure, to give a residue (12.9 g) which, after purification by silica gel chromatography (300 g; eluent:petroleum ether/isopropanol 7:3) furnishes 9.6 g of pure product.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH:5]=[C:6]2[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C2CCC(=O)C1C2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)C2CC=C(N3CCCC3)C1C2
Yield: 95.1 %

Procedure:
A solution of 30 g of nopinone ([α]D20 =+39.90; c=8 in ethanol), 29 g of pyrrolidine and 0.4 g of p-toluene-sulfonic acid in 150 ml anhydrous benzene was heated at reflux for 40 h under nitrogen atmosphere in a vessel fitted with a water separator. After evaporation of the solvent and distillation of the residue, there were obtained 39.5 g (95% yield) of 1-(6,6-dimethylnorpin-2en-2-yl)-pyrrolidine having b.p. 117°-118° C./10 Torr.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=O.[CH3:13][C:14](OC(C)=O)=[O:15]>CO.N1C=CC=CC=1.[Pd]>[CH2:8]1[C:9]2[C:5](=[C:4]([NH:1][C:14](=[O:15])[CH3:13])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1cccc2c1CCC2
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of commercially available 4-nitroindane (10 g, 61.3 mmol) and 10% Pd/C (1 g) in MeOH (200 mL) was stirred vigorously under an atmosphere of hydrogen overnight at rt. The reaction was filtered through a pad of Celite® and concentrated, and residual solvent was removed by combining the reaction with toluene followed by evaporation. The crude reaction was taken up in pyridine (100 mL), and Ac2O (20 mL) was added and the reaction stirred for 16 h at rt. The reaction was evaporated and the crude product was purified by flash chromatography (5% MeOH in EtOAc/hexane(1:1) to give the title compound (9.12 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].F[C:17]1[CH:26]=[N:25][C:24]2[C:23]([NH2:27])=[N:22][CH:21]=[N:20][C:19]=2[CH:18]=1>CN(C=O)C>[NH2:27][C:23]1[C:24]2[N:25]=[CH:26][C:17]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:18][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Nc1ncnc2cc(F)cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cnc3c(N)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.181, 32 mg) is dissolved in 1 mL DMF. To this solution is added sodium hydride (60% suspension in mineral oil, 0.229 mmol, 9.18 mg) and the mixture is stirred at rt for 5 min. and then 7-Fluoro-pyrido[3,2-d]pyrimidin-4-ylamine (0.164 mmol, 27 mg) is added. The reaction mixture is stirred at 50° C. for 22 h. The reaction mixture is cooled and quenched by pouring into 20 mL sat. NH4Cl aq. and extracted 3 times with 5 mL CH2Cl2. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-15% MeOH in DCM. 1-(4-Amino-pyrido[3,2-d]pyrimidin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one is isolated (12 mg, LC/MS m/z=322 [M+H]+) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]1([S:43](Cl)(=[O:45])=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:45])=[O:44])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.159 g (0.7 mmol) of 1-naphthalenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 47 mg. MS (ES+): m/e=541.3 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17](=[O:22])[C:18](Br)([F:20])[F:19])[CH3:15]>[Cu].CS(C)=O>[CH2:14]([O:16][C:17](=[O:22])[C:18]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([F:20])[F:19])[CH3:15]
Reactant: Ic1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(-c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 4-iodobiphenyl (Compound 1g; 840.3 mg, 3.0 mmol), bromodifluoroacetic acid ethyl ester (609.0 mg, 3.0 mmol), copper powder (381.0 mg, 6.0 mmol) and DMSO (6.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 24 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(biphenyl-4-yl)-2,2-difluoroacetic acid ethyl ester (Compound 2g) was obtained with a yield of 65%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20].O>CN(C=O)C>[CH3:17][N:18]([CH3:22])[C:19](=[S:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=S)Oc1ccc(I)cc1
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
To a stirred solution of p-iodophenol (20.0 g, 90.9 mmol) in 1) in DMF (200 mL) was added 1,4-diazabicyclo[2,2,2]octane (20.4 g, 181.8 mmol) and dimethylthiocarbamoyl chloride (16.9 g, 136.4 mmol). The resulting solution was stirred for 3.5 hr at 75° C. After cooling, 300mL of water was added. The solid was collected with suction and was dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na2SO4, and evaporated under a reduced pressure. The crude solid was recrystallized from H2O to give the 26.75 g (96%) O-p-iodophenyl dimethylthiocarbamate as a pale a yellow crystalline powder. IR (KBr) 1479, 1207, 827 cm−1; 1H-NMR (400 MHz, CDCl3) δ3.37 (s, 3H), 3.45 (s, 3H), 6.83 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H); MS (FAB) m/z 307 (M++1); Anal. Calcd. for C9H10INOS: C, 35.19; H, 3.28; N, 4.56. Found: C, 35.17; H, 3.35; N, 4.44.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[O:32]1[CH2:33][CH2:34][N:29]([CH2:24][C:23]2[CH:22]=[C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1cccc(CN3CCOCC3)c1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (40 mg, 0.11 mmol), morpholine (28 mg, 0.33 mmol) and acetic acid (33 mg, 0.55 mmol) in methanol (50 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium triacetoxyborohydride (35 mg, 0.16 mmol) was added. After the addition, the mixture was stirred at 0° C. for 2 hr. Methanol was removed under reduced pressure. The residue was resolved with 1N hydrochloric acid and washed with ethyl acetate. The mother liquor was adjusted to pH=8 and extracted with ethyl acetate. The solvent was removed to give 8-(3-(morpholinomethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (31 mg, yield 66%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.23-2.24 (m, 4H), 3.32-3.43 (q, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.13-7.19 (m, 6 H), 7.21-7.25 (m, 1H), 7.31-7.33 (m, 1H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H). LC-MS (ESI) m/z: 439 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH2:23][CH3:24])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:10]3[N:9]([CH2:23][CH3:24])[C:8]4[CH:25]=[CH:26][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)[S:14][C:15]=2[CH:21]=1
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 90 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (803.0 mg) was prepared by following General Procedure E starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid methyl ester (926.0 mg) and sodium hydroxide (2.0 N solution, 2.0 mL) MeOH (1.0 mL) and THF (2.0 mL).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[S:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[S:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A suspension of 0.2 g (0.469 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.17 g (0.775 mmol) of 2-(piperazin-1-yl)-benzothiazole, 0.1 g of potassium carbonate and 1 ml of water in 10 ml of acetonitrile is stirred for 10 hours at ambient temperature. The reaction mixture is then poured onto water, extracted with dichloromethane and the organic phase is dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: dichloromethane/acetone =20:1, then dichloromethane/methanol=20:1).
Reaction SMILES: [H-].[Na+].CO.[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C:20]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[CH:21]N(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(F)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To an oven-dried round bottom flask was added 1.87 g of a 60% oil dispersion of NaH (46.8 mmol), DMF (50 mL), and methanol (1.89 mL; 46.8 mmol) under a N2 atmosphere. To this suspension was added a solution of 2-cyanoacetamide (1.97 g; 23.4 mmol) in DMF (10 mL) via syringe followed by a solution of the crude product of Step B (21.3 mmol) in DMF (20 mL). The resulting reaction mixture was heated to 95° C. and stirred for 3 hours. The reaction was the quenched with saturated aqueous NaHSO4 solution and extracted with methylene chloride (3×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by trituration in ethanol. The precipitate was collected and washed with cold ethanol to afford the desired product: m/e=359 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21].[Br:22]N1C(=O)CCC1=O.O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:14]([Br:22])=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)cc1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)c(Br)c1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.138 g, 0.481 mmol) in anhydrous N,N-dimethylformamide (4.8 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, treated with N-bromosuccinimide (0.94 g, 0.53 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was poured into a water solution of 10% K2CO3 and extracted with EtOAc. The organic layer was washed with water and evaporated under vacuum. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 20% EtOAc in hexanes, to afford 7-amino-8-bromo-9a-butyl-6-fluoro-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.089 g, 50%) as a yellow solid.