Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:21])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:8]=1.[Cl:22]N1C(=O)CCC1=O>C1COCC1>[Cl:22][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)[C:5]=1[CH3:21]
Reactant: Cc1c[nH]c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cc1[nH]c(Cl)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
[4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine (80 mg, 0.28 mmol) was dissolved in THF (4 mL) and cooled to −60° C. N-Chlorosuccinimide (41 mg, 0.31 mmol) was dissolved in THF (2 mL) and added dropwise, keeping the internal temperature ≦−50° C. The mixture was stirred for 30 min with cooling then evaporated in vacuo. The residue was treated with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo. The crude product was purified by SiO2 chromatography (heptane/EtOAc gradient elution) to afford the title compound (37 mg) as an orange solid after recrystallisation from iPr2O. M.p. 200–203° C. MS: [M+H]+=317.7 (C16H14ClFN4 requires 316.8). 1H-NMR (CDCl3) δ: 2.17 (s, 3H, CH3), 2.42 (s, 3H, CH3) 6.77 (d, 1H, J=5.9 Hz, pyrimidinyl-H), 7.02–7.06 (m, 3H, Ph-h, NH), 7.54–7.56 (m, 2H, Ph-H), 7.95 (br. s, 1H, NH), 8.25 (d, 1H, J=5.4 Hz, pyrimidinyl-H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O>CS(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)CCNC3=O)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (0.99 g) prepared according to the method described in J. Med. Chem., Vol. 39, 4583–4591 (1996) was dissolved in dimethyl sulfoxide (2.5 ml). N-t-Butoxycarbonylpiperazine (3.4 g) was added to the solution, and the mixture was stirred at 120° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-3,4-dihydro-2H-isoquinolin-1-one (0.495 g, 24.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[CH:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:12]1([CH2:11][C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cc3cc(F)ccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2[nH]c(CN3CCCNCC3)cc2c1
Reaction time: 1 h

Procedure:
The product from Example 11B (0.48 g, 1.40 mmol) in CH2Cl2 (20 mL) was treated with TFA (20 mL) and stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (10% MeOH/CH2Cl2/1% NH4OH) to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 1.85–1.98 (m, 4H), 2.58–2.68 (m, 2H), 3.45–3.57 (m, 4H), 3.67 (s, 2H), 6.25 (s, 1H), 6.75–6.90 (m, 1H), 7.10–7.25 (m, 2H); MS (DCI/NH3) m/z 248 (M+H)+.
Reaction SMILES: [C@H:1]1([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.[O-:23][Mn](=O)(=O)=O.[K+]>CC(C)=O>[O:23]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:1]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:2][CH2:3]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCCc2ccccc21
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@@H](N2C(=O)c3ccccc3C2=O)c2ccccc21
Reaction time: 8 h
Yield: 3.4 %

Procedure:
To a solution of (R)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione (3.9 g) in acetone (60 mL) at 0° C. was added MgSO4.7H2O (11.5 g) and water (20 mL). Then KMnO4 (11.5 g) was added portionwise over the period of 2 h and stirring continued at room temperature overnight. The brown solid was filtered off and the filtrate treated with saturated sodium metabisulfite, filtered, and extracted with CH2Cl2. The combined organic layer was washed with distilled water and saturated brine, dried over MgSO4, and concentrated in vacuo. The resultant was chromatographed on silica gel (EtOAc/hexane, 25/75) to afford 0.14 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:29]C)[C:10](=[O:28])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:31].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:29])[C:10](=[O:28])[N:11]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:31]
Reactant: COc1c2c(c(C(=O)N(C)C)n(-c3ccc(C)cc3)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(-n2c(C(=O)N(C)C)c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-(3-chloro-4-fluorobenzyl)-4-methoxy-N,N-dimethyl-2-(4-methyl-phenyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (0.054 g, 0.108 mmol) in anhydrous dichloromethane (10 mL) was treated with a solution of boron tribromide (0.3 mL, 1M) in dichloromethane. The reaction mixture was stirred at room temperature for 3 hours. The product mixture was concentrated under vacuum, and the residue subject to preparative reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provide the titled compound.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[Cl:20][C:21]1[CH:45]=[CH:44][CH:43]=[CH:42][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=[CH:26][N:25]=1>COCCOC>[Cl:20][C:21]1[CH:45]=[CH:44][CH:43]=[CH:42][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=[CH:11][C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])=[CH:26][N:25]=1
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Reactant: COc1ccc(C(=O)c2ccc(Oc3ccccc3Cl)nc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Oc3ccccc3Cl)nc2)cc1OC
Yield: 31.7 %

Procedure:
In 1,2-dimethoxyethane (10 ml) was suspended 60% sodium hydride (dispersion in paraffin) (132 mg). To the suspension was added dropwise, while stirring, a solution of diethylphosphonoacetic acid morpholide (688 mg) in 1,2-dimethoxyethane (5 ml). To the mixture was added 2-(2-chlorophenoxy)-5-(3,4-dimethoxybenzoyl)pyridine (800 mg), which was heated for 8 hours under reflux. The reaction mixture was concentrated and the residue was dissolved in ether, washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to leave an oily substance, which was purified by means of a silica gel chromatography (eluted with ethyl acetate) to obtain 4-[3-(2-(2-chlorophenoxy)-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (Compound No.1) (330 mg) as a resinous solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20](B(O)O)[CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[C:21]([C:2]2[N:6]3[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: FC(F)(F)c1ccc2ncc(Br)n2c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc2ncc(-c3cccnc3Cl)n2c1
Temperature: 95 °C

Procedure:
To a solution of 3-Bromo-6-trifluoromethyl-imidazo[1,2-a]pyridine (1 eq, 2.9 mmol, 0.77 g), 2-chloropyrid-4-yl boronic acid (1.05 eq, 3.05 mmol, 0.478 g), Na2CO3 (2 eq, 5.81 mmol, 0.616 g) in dioxane (45 ml) and water (13.5 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.03 mmol, 200 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=297/299.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:10][CH2:9][C@H:8]1[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5][C@@H:4]1[N:1]=[N+:2]=[N-:3])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 2 h

Procedure:
To a solution of 3'-azido-3'-deoxythymidine (AZT) 20 g) in pyridine (50 mL) at ambient temperature, acetyl chloride (2.1 equivalents) was added. The reaction was stirred for two hours and kept at 0° at 5° C. for 20 hours. It was poured onto ice water with stirring. The aqueous phase was decanted. The oily product was dissolved in ethyl acetate and extracted with water (5 times), 0.5 N hydrochloric acid, water (2x), and dried over magnesium sulphate. The solution was filtered and evaporated in vacuo. The residual oil was dissolved in chloroform, applied to a silica gel column, and flash chromatographed using 2% methanol in chloroform. Fractions with product were evaporated and the oil was chromatographed again using ethyl acetate:hexane (6:4 v/v). Fractions with product were evaporated in vacuo to give 5'-O-acetyl-3'-azido-3'-deoxythymidine as a white solid.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:14]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[C:29]1([N:35]2[C:39]3([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:38](=[O:45])[NH:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN(C)C=O>>[O:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH:13]1[CH2:12][N:42]1[CH2:41][CH2:40][C:39]2([N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][NH:37][C:38]2=[O:45])[CH2:44][CH2:43]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1CCc3ccccc3O1)CC2
Yield: 54.6 %

Procedure:
The mixture from 31.8 g (0.1 mol) of 2-tosyloxymethyl-chroman, 7.1 g (0.07 mol) of anhydrous sodium carbonate and 23.1 g (0.1 mol) of 1-phenyl-1,3,8-triazaspiro[4.5]-decan-4-one in 240 mol of anhydrous dimethylformamide (DMF) is stirred at 110° C. for 6 h and then poured onto ice (500 g). After extracting with ethyl acetate (5×100 ml), washing the organic extracts with water, drying over anhydrous sodium sulphate and evaporating the organic phase in a water jet vacuum, 65.7 g of solvent-containing crystalline crude product are obtained which, recrystallised twice from ethyl acetate, yields 20.6 g of the title compound of m.p. 192-193.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:19]C(N)=O.CS(C)=O.[OH-].[Na+]>O>[CH3:17][CH:16]([CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:19])[C:11]=2[N:12]=[CH:13]1)[CH3:18]
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 80 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline (II) (4 g, 0.0154 mol), urea (18.5 g, 0.308 mol, 20 equiv.) and DMSO (26 ml) was heated under stirring at 145-150+C for 24 hours. Then, the reaction mixture was cooled to 80° C. and water (52 ml) and 46% aqueous NaOH solution were added to produce a pH of 10-11. The mixture was stirred at ambient temperature for 1 hour and a precipitate was collected by filtration. The wet compound was treated with water (25 ml) at 70-80° C. under stirring for 1 hour. A solid was collected by filtration from the hot mixture, washed with water (3×20 ml) and methanol (20 ml) and dried at 80° C. under reduced pressure overnight to yield 3.13 g of crude imiquimod in 84.8% yield, having a purity of 99.4% by HPLC, (containing 0.6% of the compound II). The crude imiquimod was purified by the method presented in Example 1 to obtain 2.75 g of imiquimod in 87.8% yield; total yield: 74.4%; having a purity of 99.93% (by HPLC).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:28])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=3)=[CH:12][O:13]2)=[CH:8][CH:7]=1>Cl>[C:24]([CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:11]2[C:10](=[O:28])[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:7][CH:8]=3)[O:13][CH:12]=2)=[CH:21][CH:20]=1)([OH:26])=[O:25]
Reactant: COC(=O)COc1ccc(-c2coc3cc(OCC(=O)OC)ccc3c2=O)cc1
Agent: Cl
Product: O=C(O)COc1ccc(-c2coc3cc(OCC(=O)O)ccc3c2=O)cc1
Temperature: 90 °C
Yield: 85.7 %

Procedure:
To mixture of [3-(4-Methoxycarbonylmethoxy-phenyl)-4-oxo-4H-chromen-7-yloxy]-acetic acid methyl ester 52 (45 grams, 113.5 mmol) and concentrated hydrochloric acid (250 mL) was heated at 90° C. for 5 hours. The reaction mixture was cooled to room temperature and poured onto ice water (250 mL), filtered the solids, washed with water, methanol and dried. Crude 97 was recrystallized from Dimethyl formamide and Precipitated with water to give pure 97 (36 grams, 86.1%) as a white powder. M.p: 270-272.2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]=[C:12](NC=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.Cl.[OH-:23].[Na+].O>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:23]
Reactant: [OH-]
Reactant: COc1cccc(C=C(NC=O)c2ccncc2)c1OC
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(CC(=O)c2ccncc2)c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of N-[2-(2,3-dimethoxyphenyl)-1-(4-pyridinyl)vinyl]formamide (45.2 g, 0.16 mol) in methanol (400 ml), cooled to 0° C., was added, dropwise, concentrated HCl (120 ml). After complete addition, the temperature was raised to between 35-40° C. for 2 h. The reaction was allowed to stand at ambient temperature for 1 h, and after cooling it in an ice bath, 50% aqueous NaOH was added dropwise until the mixture was basic. Water was added and the resulting white precipitate was collected to yield the desired ketone which was removed and recrystallized twice from isopropanol to afford the titled compound as a white solid, mp 99-101° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]([CH3:35])([CH3:34])[S:30][CH2:29]1.CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[C:32](=[O:33])[C:31]([CH3:34])([CH3:35])[S:30][CH2:29]4)[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC1(C)SCN(CCCCBr)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)SCN(CCCCN2CCN(c3n[nH]c4cc(F)ccc34)CC2)C1=O
Yield: 34.6 %

Procedure:
To a stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (4.4 g), K2CO3 (2.8 g), 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (6.6 g) and dimethylformamide (75 ml) was heated at 75° for 4 hours. The reaction was poured into H2O, and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed (H2O), dried (MgSO4) and the solvent concentrated to afford an oil. Upon standing the oil crystallized, and when the mass was triturated with ether, 3.3 g of a solid was collected. The compound was recrystallized from toluene-hexane to yield 2.8 g of 3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)-butyl)-5,5-dimethyl-4-thiazolidinone, m.p. 123°-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Oc2ccc3ccccc3n2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Oc3ccc4ccccc4n3)cc2)ccc1Cl

Procedure:
2-(4-Aminophenoxy)quinoline (2.4 mmoles, 0.56 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (2.4 mmoles, 0.57 g) were reacted according to procedure C to yield the title compound, 0.8 g. 70%. Mass Spec (FD) 473. Calculated for C23H15ClF3N3OS: C, 58.29; H, 3.19; N, 8.87. Found: C, 58.47; H, 3.48; N, 8.85.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([CH:23]([OH:25])[CH3:24])=[CH:18][C:17]=3[Cl:26])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1>CN(C=O)C.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:26][C:17]1[CH:18]=[C:19]([CH:23]([OH:25])[CH3:24])[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=3)[CH:28]=[CH:27][C:5]=2[N:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
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: CN(C)C=O
Product: CC(O)c1cc(Cl)c(Nc2nc3ccc(-c4cnn(C)c4)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (Examples 94 and 95, Step 3) (300 mg, 0.63 mmol) in DMF (3 mL) were added sodium carbonate (0.3 mL, 2 M) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), followed by tetrakis(triphenylphosphine)palladium (0) (145 mg, 0.13 mmol). The solution was degassed by bubbling nitrogen gas for 5 min. The reaction vessel was sealed and heated to 80° C. overnight. The reaction mixture was extracted with 3:1 (CHCl3/iPrOH) and water. The organic layers were combined and dried with MgSO4, filtered, and concentrated under reduced pressure. Purification with column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded 5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}-9-(1-methyl-1H-pyrazol-4-yl)benzo[c]-2,6-naphthyridin-1(2H)-one as racemates. The enantiomers were separated using a Chiralpak AD 10 mm×250 mm column with 40% iPrOH/60% Heptane with a flow rate of 10 ml/min in a 25 min run. The first enantiomer has a retention time of 8.47 min and the second enantiomer has a retention time of 11.68 min.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[CH3:10][CH:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(O)(=O)C>[C:12]1([CH:11]([N:18]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CC(N)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(N=C(O)/C(Cl)=C(/Cl)C(=O)O)c1ccccc1
Yield: 72.2 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 12.0 g (0.1 mol) of α-methylbenzylamine are heated in 100 ml of glacial acetic acid at the boiling point for 4 hours. 100 ml of water are then added and the oil which has separated out is extracted with methylene chloride. The methylene chloride phase is separated off, washed with water, dried and evaporated. The oil which remains cystallizes. 20.8 g (77.3% of theory) of dichloromaleic acid N-1-phenylethylimide of melting point 62°-65° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:10]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][CH2:3]1.O[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([O:14][CH2:13][CH:12]([C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:20])([CH3:21])[CH2:4][CH2:3][N:2]3[CH3:1])=[CH:7][CH:8]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)N(C)CCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Yield: 62.6 %

Procedure:
A solution of 2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol (1.2 g, 4.15 mmole) in 20 mL of THF was treated with 0.69 g of methyl 4-hydroxybenzoate, 1.2 g of triphenylphosphine and 0.72 mL of diethyl azodicarboxylate (DEAD) and heated at reflux for 6 hours. The mixture was diluted with 100 mL of ethyl acetate and washed with two 50 mL portions of water and 50 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to yield 1.1 g of 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoic acid methyl ester, as a pale yellow oil.