Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[C:7]1([N:13]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[C:21]=3[C:29]3[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=3C=O)=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1COCC1>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:37]1([N:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:14]2[CH:15]=[CH:16][C:17]([C:20]3[S:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[C:21]=3[C:29]3[CH:30]=[CH:33][C:34]([CH:2]=[O:4])=[CH:35][CH:36]=3)=[CH:18][CH:19]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccccc1-c1c(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)sc2ccccc12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2c(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)sc3ccccc23)cc1

Procedure:
A solution of 4-(2-(4-(diphenylamino)phenyl)benzo[b]thiophen-3-yl)benzaldehyde (1.1 g, 0.0023 mol) was prepared in anhydrous tetrahydrofuran (75 mL). To a dry round bottom flask equipped with an addition funnel, methyltriphenylphosphonium bromide (1.22 g, 0.003 mol) was added. Tetrahydrofuran (75 mL) was added to this reaction flask and allowed to stir. Potassium tert-butoxide (0.40 g, 0.0035 mol) was then added. The solution of (2-(4-(diphenylamino)phenyl)benzo[b]thiophen-3-yl)benzaldehyde/THF was then transferred to the addition funnel via cannula. This solution was then added to the reaction flask from the addition funnel drop-wise. The reaction solution was allowed to stir for approximately 1 hour and completion was then monitored via thin-layer chromatography. Following confirmation of completion, the reaction solution was filtered through a celite/silica gel (treated with triethylamine) plug. Solvent was removed by rotary evaporation. And the resulting solids were placed under vacuum. Crude mixture was purified by chromatography. Precipitation from a minimum amount of ethyl acetate into methanol yielded 1H NMR pure product. Product obtained: 0.7 g
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:14])[O:3]1.[CH2:15]([SH:19])[CH2:16][CH2:17][SH:18].B(F)(F)F.CCOCC.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[S:18]1[CH2:17][CH2:16][CH2:15][S:19][CH:2]1[C:10]1[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[C:4]([OH:3])=[O:14]
Reactant: O=C1OC(O)c2ccc([N+](=O)[O-])cc21
Reactant: SCCCS
Agent: FB(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc([N+](=O)[O-])ccc1C1SCCCS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled mixture of the Compound 3a (5.00 g, 25.6 mmol) and propane-1,3-dithiol (2.92 g, 27 mmol) in chloroform (75 mL) was added boron trifluoride etherate (2 mL). The mixture was stirred and allowed to warm to room temperature. After stirring for 3 hours, most of the solid had dissolved. Magnesium sulfate was added to dry the solution, and stirring was continued overnight. Filtration and evaporation of the solvent afforded a light yellow solid. This material was triturated with butyl chloride to give the Compound 3b; m.p. 192°-194° C.; 1H NMR (CDCl3 +MeSO-d6 +D2O)δ1.8-2.3 (m, 2H, CH2CH2CH2, 2.9-3.2 (m, 4H, --CH2CH2CH2 --), 6.56 (s, 1H, --SCHS--), 7.6-8.8 (m, 3H, ArH).
Reaction SMILES: [OH:1][CH:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])/[CH:3]=[CH:4]/[C:5]1[N:10]=[C:9]([CH2:11][CH:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=1.[OH-:26].[Na+]>CO>[OH:16][CH:12]([CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:4]=[CH:3]/[CH:2]([OH:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:10]=1)[CH2:13][CH2:14][C:15]([OH:26])=[O:17]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(CC2CCC(=O)O2)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(CC(O)CCC(=O)O)n1

Procedure:
Under the conditions of example 2, 30 mg of 5-(6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridyl-methyl)-tetrahydrofuran-2-one in 2 ml of methanol is saponified with 1 ml of 1 n sodium hydroxide solution and worked up. 20 mg of the title compound is obtained as oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:11]2)=[CH:6][CH:5]=1.[Na:18].Br[CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:11]2)=[CH:6][CH:5]=1)[CH3:21].[Na:18]
Reactant: CCBr
Reactant: O=S(=O)(O)c1ccc2ccc(O)cc2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOc1ccc2ccc(S(=O)(=O)O)cc2c1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
A 60% dispersion of sodium hydride (0.74 g, 18.45 mmol) in mineral oil is washed with hexanes twice and suspended in 35 mL of DMF. To this mixture is added slowly via an addition funnel 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (2.5 g, 10.1 mmol) in 50 mL of DMF at room temperature. The reaction mixture is stirred for 75 min during which time mild bubbling is observed (H2 evolution). The mixture is treated with bromoethane (2.42 mL, 32.5 mmol) and stirred for 16 hours at room temperature. A little ice is added to decompose the excess NaH and the resultant mixture is concentrated in vacuo. The residue is suspended in acetone and concentrated in vacuo two times and then is dried under high vacuum. The solid is suspended in acetone, filtered and dried to yield the crude 7-ethoxynaphthalene-2-sulfonic acid, sodium salt as a beige solid. A mixture of the sulfonic acid, sodium salt (3.77 g) in 10 mL of thionyl chloride is heated at 80° C. for 2 hours. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is diluted in EtOAc and washed successively with water (2×), saturated NaHCO3 solution and saturated NaCl. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to yield 2.65 g of a crude brown oil. The crude product is purified by column chromatography in a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to afford the title compound (1.67 g, 6.17 mmol) as a pale yellow solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:10]>>[CH:8]1[C:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[CH:1]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=1
Reactant: CCOC(=O)C#N
Reactant: C#CCCCCC#C
Product: CCOC(=O)c1cc2c(cn1)CCCC2
Yield: 20.6 %

Procedure:
A solution of 1,7-octadiyne (4.00 ml, 30.1 mmol) and ethyl cyanoformate (2.95 ml, 30.1 mmol) in dry degassed 1,4-dioxane (500 ml) under argon at rt was treated with cyclopentadienyl-Cobalt(I)-dicarbonyl (0.814 g, 4.52 mmol) and then heated at reflux for 18 h. Reaction was then evaporated, treated with toluene (100 ml), re-evaporated, dissolved in DCM (100 ml), filtered through a short pad of Kieselguhr, eluting with DCM, organic extracts evaporated, chromatographed (0-100% DCM:40-60 Petroleum ether then 0-10% methanol/DCM) to give product as an impure brown oil (1.27 g, 21%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br.Br.[NH2:12][C:13]1[C:17]([NH2:18])=[CH:16][S:15][CH:14]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]=[C:28]=[S:29]>C1COCC1>[NH2:12][C:13]1[C:17]([NH:18][C:28]([NH:27][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:26])=[S:29])=[CH:16][S:15][CH:14]=1
Reactant: Cc1cccc(C)c1N=C=S
Reactant: Nc1cscc1N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=S)Nc1cscc1N

Procedure:
was obtained in a similar manner to the method specified in Example 6a) by reacting a mixture prepared from 0.74 g of N-ethyl-N,N-diisopropylamine in 40 ml of THF, 0.8 g of 3,4-diaminothiophene dihydrobromide and 0.47 g of 2,6-dimethylphenyl isothiocyanate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])([O-])=O>C(O)C.O.NN.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(C(=O)N2CCOCC2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
The compound ([13]-(132)-158) (8.63 g) prepared in Example 83 was dissolved in ethanol (400 ml), and the solution was heated to 50° C. To the suspention, a solution of 10% Pd/C (2.25 g) in ethanol and hydrazine monohydrate (4.4 ml) were added to the solution. The mixture was stirred for 30 minutes. After the reaction was completed, the catalyst was removed by filtration through celite. The solution was concentrated, and the residue was purified by silica gel column chromatography (Kieselgel 60=120 g, ethyl acetate) to obtain the above-captioned compound ([13]-(133)-158) (7.57 g) as a white solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:32]CCl>C(O)C>[ClH:32].[C:23]1([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
(R)-1-(2-((2,2-Diphenylethenyl)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (Example 50) (3.0 g, 0.079 mol) was dissolved in ethanol (20 ml) and 12 N sodium hydroxide solution (2.0 ml) was introduced. After stirring the solution at room temperature for 2.5 h, 37% hydrochloric acid (ca. 2.2 ml) was added, with acidity measured at pH 2. Dichloro-methane (300 ml) was introduced, and the mixture was dried (MgSO4). Filtration and evaporation of the filtrate gave a solid, which was triturated with diethyl ether, to give the title compound (2.65 g, 86%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].[C:16]1([CH2:22][CH2:23][C:24](Cl)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[C:16]1([CH2:22][CH2:23][CH2:24][N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[CH2:9]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(C2CCCNC2)ccc1F
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Yield: 93.1 %

Procedure:
The title compound was prepared by acylation of 209 mg (1 mmole) of the 3-(4-fluoro-3-methoxyphenyl)piperidine from Preparation 8, Part C, with 253 mg (1.5 mmole) of 3-phenylpropionyl chloride in toluene, followed by reduction with 175 mg (4.6 mmole) of lithium aluminum hydride in tetrahydrofuran, substantially according to the procedure of Preparation 3. This afforded 305 mg (93% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl[CH:19]([CH:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)[CH3:23])[CH:20]=O.C(N(CC)CC)C>C(O)(C)C>[N:30]1[C:31]2[C:26](=[CH:25][C:24]([CH:22]([C:19]3[N:3]4[N:4]=[C:5]([C:8]5[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=5)[CH:6]=[N:7][C:2]4=[N:1][CH:20]=3)[CH3:23])=[CH:33][CH:32]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1
Reactant: CC(c1ccc2ncccc2c1)C(Cl)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cnc3ncc(C(C)c4ccc5ncccc5c4)n3n2)cc1
Temperature: 110 °C
Yield: 22.5 %

Procedure:
A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (50 mg, 0.217 mmol) and 2-chloro-3-quinolin-6-ylbutanal (61 mg, 0.26 mmol) in isopropyl alcohol (3.0 mL) was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 by adding triethylamine. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel with EtOAc in methylene chloride (0-60%) to afford the desired product (0.020 g, 22%). LCMS: (M+H)=410.0.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].C([O-])(=[O:19])C.[Na+].C(=O)(O)[O-].[Na+].Cl>CS(C)=O.O>[CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[NH:7][C:6]1=[O:19])[C:2]#[C:3][CH3:4]
Reactant: CC(=O)[O-]
Reactant: CC#CCn1c(Cl)nc2nc(Cl)nc(Cl)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC#CCn1c(=O)[nH]c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
7-(2-Butynyl)-2,6,8-trichloro-7H-purine (1.0 g) was dissolved in dimethylsulfoxide (20 mL), and then sodium acetate (595 mg) and sodium bicarbonate (366 mg) were added to the mixture. This reaction solution was stirred at room temperature for 12 hours, and then 1 N of aqueous hydrochloric acid solution (5.0 mL) and 80 mL of water were added. This reaction solution was stirred at room temperature for one hour, and then a white precipitate was collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (800 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([NH2:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C@H:26]1[C:30](=[O:31])[NH:29][CH2:28][C@@H:27]1[C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:21])[F:23])[CH:14]=3)=[CH:11][C:10]([NH:24][C:32]([C@@H:27]3[C@@H:26]([CH3:25])[C:30](=[O:31])[NH:29][CH2:28]3)=[O:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Reactant: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Yield: 64.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (90 mg) in N,N-dimethylformamide (0.9 ml) were added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (50 mg) prepared in Preparation 1, HOBt.H2O (61 mg) and WSC.HCl (77 mg), and the mixture was stirred at room temperature for 2 hours. To this mixture were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (80 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>O1CCCC1.[OH-].[Na+]>[C:9]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.6 %

Procedure:
A solution of valine (20 g, 0.17 mole) in tetrahydrofuran (20 ml) and 2N NaOH (111 ml) was cooled down to 10° (ice-water bath) under nitrogen and treated dropwise with benzoyl chloride (23.8 ml, 0.21 mole). The reaction mixture was warmed up to room temperature, stirred for 3.0 hours then cooled back down to 0° (ice-salt bath) and treated with concentrated sulfuric acid (8.0 ml). The mixture was extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml), dried (anhydrous MgSO4), filtered and evaporated to dryness to give title compound as a solid (41.97 g, 100% crude yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[N:32]1([CH2:37][CH2:38][C@H:39]2[CH2:44][CH2:43][C@H:42]([NH2:45])[CH2:41][CH2:40]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:45][C@H:42]3[CH2:43][CH2:44][C@H:39]([CH2:38][CH2:37][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:40][CH2:41]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: N[C@H]1CC[C@H](CCN2CCCC2)CC1
Agent: Cl
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)N[C@H]1CC[C@H](CCN2CCCC2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and trans-4-(2-pyrrolidin-1-yl-ethyl)-cyclohexylamine dihydrochloride (Reference Example 4) according to the method described in Example 1e. MS (EI) 627.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH2:20][CH:17]3[CH2:19][CH2:18]3)[C:6]=2[CH:16]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccncc12
Reactant: BrCC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cnccc2c2ccc(Cl)cc2n1CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
To a stirred solution of 8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.434 mmol) (as prepared in Ex. 12, Part B) in anhydrous DMF (2 mL) at 0° C. was added cyclopropyl methyl bromide (0.088 g, 0.650 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to 8-chloro-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.351 mmol, 81% yield, 53% pure by LC/MS). LC/MS (ESI) m/e 285.1 [(M+H)+, calcd for C16H14ClN2O 285.1]; LC/MS retention time (method D): tR=0.91 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1>C(O)(C)C>[CH3:11][C@H:12]1[CH2:17][N:16]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CC(C)O
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A mixture of 4-chloro-3-nitropyridine (0.704 g, 4.44 mmol) and tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate (1.0 g, 4.7 mmol) in isopropyl alcohol (8.7 mL) was stirred at 75° C. overnight. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with water and extracted with EtOAc. The organic extracts were combined and evaporated under reduced pressure. The residue was purified by flash chromatography on 40 g silica gel, eluting with 0-90% EtOAc in hexanes, to give the sub-title compound as a yellow solid (1.14 g, 76.2%). LCMS calc. for C16H25N4O4 (M+H)+: m/z=337.2. found: 337.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[CH:10]=[CH:11][CH:12]=[O:13])=[CH:4][CH:3]=1.[C:28]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:29][C:30]([CH3:32])=[O:31]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:9]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:32][C:30](=[O:31])[CH2:29][C:28]([O:34][CH2:35][CH3:36])=[O:33])=[CH:6][CH:7]=1
Reactant: CCn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(CC)n1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,5-bis(4-fluorophenyl)-4-(2-ethyl-2H-tetrazol-5-yl)-2,4-pentadienal (2.0 g) in 20 mL of tetrahydrofuran at -40° C. was added 6.9 mL of 0.8M (5.5 mmoles) freshly prepared solution of ethyl acetoacetate dianion [described in Example 10]. The solution was stirred at -40° C. for 30 minutes and then allowed to warm to -10° C. After a total of one hour, the reaction was quenched with 1N HCl. The mixture was extracted with chloroform, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 0.4 g of pure title compound. MS (EI): m/e=496 for M+.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:5])[CH3:2].S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:8]=1[C:9]([Cl:27])=[O:10])=[O:5])[CH3:2]
Reactant: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)Cl)c1
Temperature: 55 °C
Reaction time: 14 h
Yield: 98.3 %

Procedure:
5.59 g (16.6 mmol) of 2-ethoxycarbonyloxy-5-octanoylbenzoic acid are dissolved in 56 ml of toluene with a few drops of pyridine. 1.45 ml (20 mmol) of thionyl chloride are added dropwise and the mixture is stirred at 55° C. for 14 hours and then concentrated to dryness. 5.79 g of 2-ethoxycarbonyloxy-5-octanoylbenzoyl chloride are obtained in a yield of 98%.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[C:14]([C:18]1[CH:27]=[CH:26][C:21]([C:22](=O)[CH2:23]Br)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:23]=2)=[CH:26][CH:27]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)cs2)cc1
Yield: 68 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 4-t-butylphenacyl bromide to obtain methyl 4-[4-(4-t-butylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 68%. Pale yellow prisms. Melting point: 154 to 155° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.C(Cl)(=O)C([Cl:22])=O.CN(C=O)C>ClCCCl>[CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12]([Cl:22])=[O:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)O)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylic acid, oxalyl chloride, DMF and DCE was stirred at room temperature for 90 minutes and then treated in the usual way to give 5-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carbonyl chloride as a brown solid.