Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].N1C=NC=N1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(C)CCN
Agent: c1nc[nH]n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A solution of methyl 4-(4-biphenylylmethoxy)phenylacetate (60.0 g), N,N-dimethylethylenediamine (47.7 g), and 1H-1,2,4-triazole (12.6 g) in toluene (120 ml) was stirred under nitrogen at 100° C. for 8 hr and cooled until the temperature of the reaction mixture was reached to 60±2° C., to which ethyl acetate (240 ml) was added for 20 min. The reaction mixture was further heated under reflux for additional 30 min, left to stand at room temperature over night and stirred in an ice bath for 2 hr. The precipitate was collected by filtration and washed with ethyl acetate (120 ml) to obtain the titled compound (71.7 g).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(=O)N)[CH:24]=3)=[C:18]([F:32])[CH:17]=2)[C:8]([C:10]2([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[N:35]1C=CC=CC=1.O.FC(F)(F)C(=O)OI(C1C=CC=CC=1)OC(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:35])[CH:24]=3)=[C:18]([F:32])[CH:17]=2)[C:8]([C:10]2([C:13]([NH2:15])=[O:14])[CH2:11][CH2:12]2)=[O:9])=[CH:33][CH:34]=1
Reactant: NC(=O)c1cc(Oc2ccc(N(Cc3ccc(F)cc3)C(=O)C3(C(N)=O)CC3)cc2F)ccn1
Reactant: c1ccncc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C1(C(=O)N(Cc2ccc(F)cc2)c2ccc(Oc3ccnc(N)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of N-(4-fluorobenzyl)-N-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 mg, 0.05 mmol) in DMF (1 mL) at room temperature was added pyridine (0.2 mL), water (0.1 mL), and [bis(trifluoroacetoxyl)-iodo]benzene (Aldrich, 34 mg, 0.08 mmol). The reaction mixture was stirred at rt for 2 h, and then quenched by adding 2 mL of methanol. The reaction mixture was purified by prep. HPLC. The desired fractions were combined, neutralized with aq. K2HPO4, concentrated and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in a small amount of CH3CN/H2O and lyophillized to dryness to give the title compound (21 mg, 90%) as a white solid. 1H NMR (DMSO-d6) δ 10.87 (br s, 1H), 8.44 (t, 1H, J=6.0 Hz), 7.91 (d, 1H, J=6.6 Hz), 7.88 (d, 1H, J=13.2 Hz), 7.37-7.29 (m, 6H), 7.13 (t, 2H, J=8.8 Hz), 4.29 (d, 2H, J=6.1 Hz), 1.38 (d, 4H, J=2.2 Hz); MS (ESI+) m/z 439.14 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=3[C:6]3[C:14]2=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=3)=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1cccc2c3c([nH]c12)CCCC3=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Cc1cccc2c3c(n(Cc4ccc(F)cc4)c12)CCCC3=O
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
8-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1967 g, 0.99 mmol) is added to a slurry of pentane-washed NaH (0.0449 g, 0.0011 mol) in DMF (2 mL). After stirring for 30 min, p-fluorobenzyl bromide (0.15 mL, 0.0012 mol) is added. Starting material is still present after 3 h, so additional p-fluorobenzyl bromide (0.015 mL, 0.12 mmol) is added and the mixture is stirred overnight. The mixture is then partitioned between aq. sodium bicarbonate and ethyl acetate and the organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (75 mL) using methanol/dichloromethane (2/98). The impure fractions are rechromatographed on silica gel (60 mL) using methanol/dichloromethane (2/98). The pure fractions are combined and recrystallized from ethyl acetate/hexane/dichloromethane to give 0.1021 g (34%) of the title compound; mp 154-155° C.; MS (ESI+) for C20H18FNO m/z 308.2 (M+H)+; IR (drift) 1635, 1602, 1539, 1510, 1462, 1449, 1414, 1226, 1159, 835, 826, 801, 786, 756, 747 cm−1; 1H NMR (CDCl3) δ2.21, 2.51, 2.59, 2.81, 5.55, 6.87, 6.98, 7.17, 8.23. Anal. Calcd for C20H18FNO: C, 78.15; H, 5.90; N, 4.56. Found: C, 77.72; H, 5.95; N, 4.64.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.O.[NH2:21][NH2:22].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CCC>[NH:21]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1)[NH2:22]
Reactant: NN
Reactant: COc1cc(-c2ccc(Cl)nn2)ccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: COc1cc(-c2ccc(NN)nn2)ccc1OC(F)F
Temperature: 80 °C
Yield: 93.4 %

Procedure:
20.0 g (69.8 mmol) of 3-chloro-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine are boiled under reflux in 100 ml of n-butanol with 17 ml (350 mmol) of hydrazine hydrate for 8 hours. The solution is cooled to about 80° C. and stirred with 100 ml of saturated sodium carbonate solution and 200 ml of water. The precipitate is filtered off with suction, washed with water and dried in vacuo. 18.4 g (93.4%) of 3-hydrazino-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine of m.p. 154° C. are obtained.
Reaction SMILES: O1CCOCC1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=1[O:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>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.O>[N+:25]([C:21]1[C:20]([O:28][CH3:29])=[C:19]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: COc1c(Br)cccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C=O)cc2)cccc1[N+](=O)[O-]
Yield: 79.7 %

Procedure:
To a solution of 60 mL of 1,4-dioxane and 10 mL of water was added 4-formylphenylboronic acid (3.0 g, 0.02 mol), followed by 1-bromo-2-methoxy-3-nitro-benzene 1c (4.64 g, 0.02 mol), tetrakis(triphenylphosphine)palladium (1.15 g, 1 mmol) and sodium carbonate (4.24 g, 0.04 mol). Upon completion of the addition, the mixture was heated to reflux for 5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 3′-nitro-2′-methoxy-biphenyl-4-carbaldehyde 32a (4.1 g, 80.4%) as a yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)C1C=CC=CC=1.[N:25]1[C:34]2[C:29](=[N:30][C:31]([CH:35]=O)=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.N1CCCCC1>CC(O)C>[C:21]([O:20][C:18](=[O:19])[NH:17][C:12]1[NH:11][C:15](=[CH:35][C:31]2[CH:32]=[CH:33][C:34]3[C:29](=[CH:28][CH:27]=[CH:26][N:25]=3)[N:30]=2)[C:14](=[O:16])[N:13]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C

Procedure:
To a mixture of 2-tert-butoxycarbonylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (53.3 mg, 0.16 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration to give (5-[1,5]-naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-carbamic acid tert-butyl ester as a yellow solid, 29.8 mg (54.9%). HR-ES (+) m/e calcd. for C17H17N5O3: (M+H)+ 340.1404. Found: 340.1404.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:24])(=[O:23])[NH:10][C:11]3[C:20]2=[CH:19][CH:18]=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4].C(Cl)(Cl)[Cl:26]>>[CH3:1][O:2][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:24])(=[O:23])[NH:10][C:11]3[C:20]2=[CH:19][C:18]([Cl:26])=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Reactant: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 57 %

Procedure:
In a similar fashion using route 51 general procedure 117,6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid methyl ester 307 (1.1 g, 3.2 mmol), 1,3-dichloro-5,5-dimethylhydantion (765 mg, 3.8 mmol) in chloroform (40 ml), gave the title compound (1.6 g, 57%) after washing with MeOH/DCM.
Reaction SMILES: NC1C=CC=CC=1N[S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].C[O:22]C1C=CC(S(C(C)C)(=O)=O)=CC=1S(Cl)(=O)=O>C(Cl)Cl.N1C=CC=CC=1>[S:16]1[C:12]([S:9]([OH:10])(=[O:11])=[O:22])=[CH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]1=2
Reactant: COc1ccc(S(=O)(=O)C(C)C)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 214.7 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol) (prepared as in example 1) in DCM (2 mL) and pyridine (2 mL), 2-methoxy-5-(propane-2-sulfonyl)benzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 460 mg of benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(propane-2 sulfonyl) benzenesulfonylamino]phenyl-amide. Tr 1.09 min; MS: 581.4 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 0.97 (d, 6H), 3.58 (m, 1H), 4.02 (s, 3H), 6.84 (dd, 1H), 7.96 (td, 1H), 7.10 (td, 1H), 7.23 (dd, 1H), 7.44-7.54 (m, 3H), 7.86 (d, 1H), 7.90 (s, 1H), 7.96 (d, 1H), 8.03 (dd, 2H), 9.22 (bs, 1H), 9.79 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15](=[O:20])C(F)(F)F)=[CH:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[OH-:21].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([OH:20])=[O:21])=[CH:7][N:8]2[CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 1-(6-chloro-1-isobutyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (282.7 mg, 0.81 mmol) in a 20% aqueous sodium hydroxide solution (2.7 mL) was heated under reflux for 17 h. At this time, the reaction was cooled to 25° C. and was diluted with water (75 mL). This mixture was extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-isobutyl-1H-indole-3-carboxylic acid (161.4 mg, 79%) as a cream-colored solid: mp 205-206° C.; EI-HRMS m/e calcd for C13H14ClNO2 (M+) 251.0713, found 251.0713.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24]>O1CCCC1>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(Br)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(Br)c1
Yield: 64.7 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 7 ml of water and 1.5 ml of tetrahydrofuran in place of the methanol, and 190 mg of 3-bromo-4-fluoroaniline in place of the 3-(tert-butyl)aniline. 266 mg of N-(3-bromo-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:14])[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>O1CCCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([OH:14])([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: COc1ccc([Mg]Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in oil, 0.3 g, 7.5 mmol) (Aldrich) was added to a suspension of 6-chloroisatin (1.82 g, 10 mmol) in tetrahydrofuran (30 mL) under argon with cooling in a −25° C. bath and magnetic stirring. After 10 minutes, a solution of 4-methoxyphenyl magnesium bromide in tetrahydrofuran (0.5 M, 40 mL, 20 mmol) (Aldrich) was added dropwise at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 2 hour, 15% aqueous ammonium chloride solution (25 mL) and water (50 mL) were added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-hydroxy-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCO>[N+:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C(O)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
3-Fluoro-4-nitrobenzoic acid (Combi-Blocks CA-4022, 5 g; 27.01 mmol) was dissolved in EtOH (30 mL) to which was added piperidine (8.02 mL; 81.03 mmol). The reaction mixture was stirred at RT for 24 hours, then concentrated and the residue was taken up in water (300 mL). The aqueous phase was washed with Et2O then the aqueous phase was acidified with acetic acid until pH 5. The aqueous phase was extracted with Et2O (900 mL). The combined organic phases were dried over MgSO4 and concentrated affording the title compound as an orange solid (6.18 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 13.55 (br s, 1H), 7.89-7.86 (d, J=8.42 Hz, 1H), 7.77-7.76 (d, J=1.40 Hz, 1H), 7.60-7.57 (dd, J=8.42 Hz, 1.50 Hz, 1H), 3.23-2.98 (m, 2H), 3.21-3.05 (m, 4H), 1.63-1.58 (m, 6H). HPLC (Method A) Rt 3.88 min (Purity: 99.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:5]1[C:4]([OH:9])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: Oc1cc(Cl)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Product: Oc1cc(Cl)cnc1Cl
Temperature: 180 °C

Procedure:
A mixture of 5-chloro-2,3-dihydroxypyridine (1.0g.) and phosphoryl chloride (10ml.) was heated overnight at 180°C. in a sealed tube. The phosphoryl chloride was distilled off, and the residue was chromatographed, to give 2,5-dichloro-3-hydroxypyridine, m.p. 160°-161°C. (ethyl acetate - petrol).
Reaction SMILES: [CH2:1]([O-:3])[CH3:2].Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(Cl)(=O)C>>[C:1]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=[O:3])[CH3:2]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CC[O-]
Agent: Cl
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 78.3 %

Procedure:
Beginning with 2.00 gm (5.74 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole dihydrochloride ethanolate and 1.13 gm (25.8 mMol) acetyl chloride, 1.22 gm (78.3%) of the title compound were recovered as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([C:31]#[N:32])=[C:12]([CH2:20]C3C4C(=CC=CC=4)C=CC=3)[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]2[S:7][CH2:6]1)=[O:4].COC([C@H]1N2C(=O)C(Br)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3C=CC=CC=3)=C2SC1)=O.COC([C@H]1N2C(=O)C(Br)=C(C)C(C3C=CC=CC=3)=C2SC1)=O>>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([C:31]#[N:32])=[C:12]([CH3:20])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(C)c(Br)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(Br)c(=O)n21
Product: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(C)c(C#N)c(=O)n21
Yield: 86 %

Procedure:
By following the procedure described for the preparation of 6a from 5a, 5c (150 mg, 0.39 mmol) gave 6c as a pale yellow foam (110 mg, 86%): [α]D−161 (c 1.0, CHCl3); IR λ 3012, 2956, 2215, 1749, 1648, 1440, 1365, 1257, 1216 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.50-7.39 (m, 3H), 7.25-7˜(m, 2H), 5.72 (dd, J=8.8, 2.3, 1H), 3.85 (s, 3H), 3.72 (dd, J=11.9, 8.8, 1H), 3.51 (dd, J=11.9, 2.3, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6, 158.8, 158.4, 154.3, 135.0, 129.7, 129.5, 129.1 (splitted), 128.9, 116.5, 115.4, 99.5, 64.1, 53.5, 31.7, 20.0; HRMS (FAB+) calcd for C17H15N2O3S 327.0803, obsd 327.0805.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@H:12]([CH3:17])[C:13]([O:15]C)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[C@H:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:17]
Reactant: COC(=O)[C@@H](C)Oc1cccc2cccnc12
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Solvent: CCO
Product: C[C@@H](Oc1cccc2cccnc12)C(=O)NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a stirred mixture of (R)-methyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.433 mmol) in EtOH (1 mL) was added (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (89.2 mg, 0.433 mmol). The mixture was stirred in a sealed tube in a microwave apparatus at 120° C. for 0.5 hour. After cooling to room temperature the solvent was evaporated, and the residue was first purified by prep-TLC and then prep-HPLC to afford the title compound (90 mg, yield: 51%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.89 (br. S., 1H), 8.29-8.42 (m, 1H), 7.49-7.65 (m, 3H), 7.28 (d, J=5.52 Hz, 1H), 6.89-7.13 (m, 4H), 5.01-5.13 (m, 1H), 4.10-3.84 (m, 1H), 3.45-3.60 (m, 2H), 3.35-3.43 (m, 2H), 2.81 (d, J=3.01 Hz, 2H), 2.65 (br. S., 2H), 2.34-2.49 (m, 2H) 1.71 (d, J=6.78 Hz, 3H), LCMS (m/z): 406.2 [M+H]+
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:4]([OH:12])[O:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:12][CH:4]1[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:6][CH:2]([CH3:1])[O:3]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC2(CCCCC2)C(O)O1
Solvent: c1ccncc1
Product: CC(=O)OC1OC(C)CC12CCCCC2
Temperature: 50 °C

Procedure:
A mixture of 11 g of 3-methyl-2-oxaspiro[4.5]decan-1-ol, 7.7 g of pyridine and 9.2 g of acetic anhydride was heated at 50° C. for 12 hours. The reaction mixture was concentrated. The concentrate was purified by distillation, obtaining 13 g (yield 960) of the target compound, 3-methyl-2-oxaspiro[4.5]decan-1-yl acetate.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[N+:27]([C:18]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[N:13]1[C:14](=[O:15])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Eight-tenths mole (157.6 g.) of 1,8-naphthalimide, 260 g. (1.15 m.) of 4-chloro-3-nitrobenzotrifluoride, 64 g. (0.46 m.) of anhydrous potassium carbonate, about 4 g. (0.024 m.) of potassium iodide, and 2400 ml. of dry N,N-dimethylformamide were allowed to reflux under a nitrogen atmosphere for about 8 hours. The reaction mixture was allowed to cool to room temperature and the reaction vessel was then chilled in an ice-bath. The resulting precipitate was filtered, washed with water, and dried in vacuo to yield crude 2-[2-nitro-4-(trifluoromethyl)phenyl]-1H-benz[de]isoquinoline-1,3-(2H)-dione.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15](Cl)[C:14]=1[N+:24]([O-:26])=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[OH-].[NH3:29]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([NH2:29])[C:14]=1[N+:24]([O-:26])=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Reactant: N
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate (63 gm 160 mmol) was dissolved in tetrahydrofuran (300 mL) and to this was added concentrated ammonia hydroxide solution (0.88 specific gravity, 100 mL) to give two phases. This was transferred to a pressure vessel, sealed and heated to 80° C. with stirring for 2 hours. The tetrahydrofuran was evaporated and the residue was partitioned between saturated brine and diethyl ether. The organic extracts were dried over sodium sulphate, filtered and evaporated to give a thick yellow slurry (65 gm) of ethyl-[2-amino-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate.