Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[C:13]([F:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([F:22])=[C:14]([S:18]([NH:8][C:5]2[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1F

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.16 g) and 3-chloro-2-fluorobenzenesulphonyl chloride (0.27 g). Yield 0.22 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:37]([NH2:39])=O.S(Cl)(Cl)=O>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[N:23][N:22]=4)=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:37]#[N:39]
Reactant: COc1cc2nccc(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2cc1C(N)=O
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2cc1C#N
Temperature: 80 °C

Procedure:
7-Methoxy-4-(4-(4-phenylphthalazin-1-ylamino)phenoxy)quinoline-6-carboxamide (125 mg, 243 μmol) and thionyl chloride (10 ml, 24341 μmol) were combined and heated to 80° C. for 3 hours. Thionyl chloride was then removed under vacuum. The mixture was then made basic with sat. sodium bicarbonate and extracted with DCM. The organic extracts were combined, dried with sodium sulfate, filtered and concentrated. The product was purified by silica gel chromatography using a 0 to 70% gradient of 90/10/1 (DCM/methanol/ammonium hydroxide) in DCM. MS: M+H+=496.
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1>ClS(O)(=O)=O>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Following the general procedure of Example 6 but making non-critical variations, 9α-hydroxyandrostenedione (20.00 g.) is reacted with chlorosulfonic acid (10 ml.) at a temperature of 20°-27° for 17 minutes. Upon workup the reaction gives androsta-4,9(11)-diene-3,17-dione, 15.9 l g., (79.5% weight yield, 84.4 % chemical yield); m.p. 200.5°-204°; [α]D +218° (chloroform); UV (methanol)λmax =240 nm (ε=15,200).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]=[N:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[C:2]([O:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:7]=1
Reactant: CCCCCCCCBr
Reactant: N#Cc1ccc(N=Nc2ccc([N+](=O)[O-])cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1cc(N)ccc1N=Nc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
10 g (37.3 mmol) of 4-((2-hydroxy-4-nitrophenyl)diazenyl)benzonitrile is dissolved in 200 mL of acetone, and 7.8 mL (44.9 mmol) of 1-bromooctane and 10.3 g (74.5 mmol) of potassium carbonate (K2CO3) are added thereto. Subsequently, the resultant reaction mixture is agitated at 60° C. for 24 hours while being refluxed, and then the temperature is lowered to room temperature. The reaction mixture is concentrated, dissolved in dichloromethane (CH2Cl2), passes through a silica gel pad, and the filtrated solution is recrystallized using dichloromethane (CH2Cl2) and n-hexane. The purified compound is dissolved in 150 mL of hot ethanol, and 12.5 g (74.4 mmol) of Na2S.5H2O dissolved in hot ethanol and water is added thereto. Subsequently the resultant reaction mixture is agitated at 80° C. for 5 hours, and then the temperature is lowered to room temperature. The resultant precipitated crystal is filtered, washed with water several times, and dried, thus obtaining 8.9 g (25.4 mmol) of 4-((4-amino-2-(octyloxy)phenyl)diazenyl)benzonitrile of the following Chemical Formula 1a-1. A yield is 68%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:20][C@H:21]1[CH2:23][C@H:22]1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:20][C@H:21]1[CH2:23][C@H:22]1[C:24]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:19])[CH:17]=2)=[O:25]
Reactant: Cc1c(F)cncc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(F)cncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 40 °C
Yield: 57.3 %

Procedure:
A mixture of 7-(5-fluoro-4-methylpyridin-3-yl)isoquinolin-3-amine (161.4 mg; 0.6372 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (80.3 mg; 0.772 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (496.9 mg; 0.9149 mmol), N,N-diisopropylethylamine (0.30 mL; 1.7 mmol), 4-(dimethylamino)pyridine (0.06372 mmol) and N,N-dimethylformamide (5 mL; 64.4 mmol) was heated at 40° C. for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 30-90% ethyl acetate in dichloromethane) followed by preparatory reverse-phase HPLC to yield 124 mg (57%) of the title compound. LCMS (ESI): RT (Min)=8.33, M+H=340.2, method=G; 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.21 (s, 1H), 8.55 (d, J=4.5 Hz, 2H), 8.42 (s, 1H), 8.13 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.78 (dd, J=8.5, 1.6 Hz, 1H), 5.06-4.85 (m, 1H), 2.34-2.27 (m, 1H), 2.26 (d, J=1.9 Hz, 3H), 1.75-1.65 (m, 1H), 1.25-1.16 (m, 1H).
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]([N:21]1[CH2:25][CH2:24][CH:23](Cl)[CH2:22]1)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[C:12]1([C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH:23]2[CH2:24][CH2:25][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22]2)[C:10]#[N:11])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: CC(C)N1CCC(Cl)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h

Procedure:
In a 2 liter, three neck, round-bottom flask fitted with pot thermometer, reflux condensor, electric stirrer and dropping funnel was placed 47.5 g. (1.22 mole) of sodium amide followed by 300 ml. of dry toluene. To this was added dropwise at 50° C. 214 g. (1.11 mole) of diphenylacetonitrile in 800 ml. of dry toluene. When addition was complete, the temperature was raised slowly to reflux and maintained for 4 hours. To the refluxing mixture was added at a rapid dropwise rate 164.9 g. (1.11 mole) of 1-isopropyl-3-chloropyrrolidine. The refluxing and stirring was continued for 3 hours, and the mixture was allowed to stand overnight. The toluene solution was washed with 1 liter of water and extracted with about 2 liters of 1 N hydrochloric acid. The aqueous layer was made basic with dilute sodium hydroxide and extracted with several portions of ether. The ethereal solution was dried over sodium sulfate, concentrated, and the residue distilled through an eight inch beaded column. Yield, 216 g. (64%); b.p. 175°-177° C./0.25 mm. The product crystallized on standing and was recrystallized from iso-octane. m.p. 73°-74° C.
Reaction SMILES: I[CH2:2][C:3](=[CH2:13])[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:9]([Si:6]([CH3:8])([CH3:7])[O:5][CH2:4][C:3]([CH2:2][O:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=1)=[CH2:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=C(CI)CO[Si](C)(C)C(C)(C)C
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(COc1ccc(OC(F)(F)F)cc1)CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 11 h
Yield: 58.2 %

Procedure:
A mixture of iodide 165 (4.63 g, 14.8 mmol), 4-(trifluoromethoxy)phenol (3.10 mL, 23.9 mmol) and powdered K2CO3 (3.56 g, 25.8 mmol) in acetone (10 mL) was stirred at 50° C. for 11 h. The resulting cooled mixture was diluted with ice-water (100 mL) and extracted with CH2Cl2 (4×100 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-3% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 5-10% CH2Cl2/petroleum ether gave tert-butyl(dimethyl)[(2-{[4-(trifluoromethoxy)phenoxy]methyl}-2-propenyl)oxy]silane (166) (3.12 g, 58%) as a colourless oil; 1H NMR (CDCl3) δ 7.12 (br d, J=9.0 Hz, 2H), 6.90 (dt, J=9.1, 2.9 Hz, 2H), 5.27 (d, J=0.7 Hz, 1H), 5.20 (d, J=1.1 Hz, 1H), 4.54 (s, 2H), 4.24 (s, 2H), 0.91 (s, 9H), 0.07 (s, 6H); HRFABMS calcd for C17H26F3O3Si m/z [M+H]+ 363.1603. found 363.1604.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Yield: 70 %

Procedure:
Stating with [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester and benzenesulfonyl chloride, and using the method analogous to the one described for example 14-1, [4-(3-benzenesulfonylamino-benzene-sulfonyl-amino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (15 mg, 70%) was obtained as a white solid. MS cald. for C23H26N4O6S2 518, obsd. (ESI+) [(M+H)+]:519.
Reaction SMILES: ClC[C:3]([N:5]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([C:27]#[N:28])[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:6][CH2:7][NH:8][C:9](=O)OC(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(Cl)Cl>[O:4]=[C:3]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][C:26]1=2
Reactant: CC(C)(C)OC(=O)NCCN(CC1CCCc2c(C#N)cccc21)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc2c1CCCC2CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-Butyl (2-{(chloroacetyl)[(5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}ethyl)carbamate (120 mg, 0.29 mmol) in DCM (5 mL) was added TFA (0.5 mL) and stirred at ambient temperature for 2 h until TLC indicated the starting material was consumed completely. The solvent was evaporated in vacuum. The residue was dissolved in ethanol (10 mL) and K2CO3 (120 mg, 0.9 mmol) and catalytic NaI was added. The reaction mixture was refluxed overnight, then the salt was removed by filtration. The filtrate was evaporated under vacuum, and then water (10 mL) and DCM (10 mL) was added. The mixture was extracted with DCM (10 mL×3), dried over anhydrous Na2SO4, and evaporated to give the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 7.42 (d, J=7.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 3.66-3.72 (m, 1H), 3.54 (s, 2H), 3.21-3.32 (m, 4H), 2.98-3.11 (m, 3H), 2.75-2.85 (m, 1H), 1.78-1.94 (m, 2H), 1.71-1.75 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([NH:8][C:9](=[O:22])[CH2:10][C:11](=[O:21])[C:12]2([CH3:20])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]2)[CH:7]=1.CN(C)C1C=CC=CC=1.[CH2:34]([S:50](Cl)(=[O:52])=[O:51])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].Cl>O1CCCC1.O>[CH2:34]([S:50]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([NH:8][C:9](=[O:22])[CH2:10][C:11](=[O:21])[C:12]2([CH3:20])[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[O:14][CH2:13]2)[CH:7]=1)(=[O:52])=[O:51])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: COc1ccc(N)cc1NC(=O)CC(=O)C1(C)COC(C)(C)OC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)c1ccccc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc(OC)c(NC(=O)CC(=O)C2(C)COC(C)(C)OC2)c1
Reaction time: 0.5 h

Procedure:
The amine product of Reaction Example 8, N-(5-amino-2-methoxyphenyl)-2,2,5-trimethyl-β-oxo-1,3-dioxane-5-propanamide, (18.5 parts) and N,N-dimethylaniline (8.5 parts) are combined in tetrahydrofuran (250 parts) and a solution of 1-hexadecylsulfonyl chloride (17.9 parts) dissolved in tetrahydrofuran (25 parts) is added dropwise with stirring, ca. 0.5 hr. The reaction is allowed to stand several hours and subsequently poured into cold water (600 parts) containing concentrated hydrochloric acid (5 parts). The crude product is extracted with ethyl ether and the ethereal layer washed once with sodium bicarbonate solution, once with water, dried over magnesium sulfate, filtered and subsequently flash evaporated in vacuo to give a light tan product in 90% of theoretical yield. Analytical samples are crystallized from ethyl alcohol, m.p. 83-85° C. Proton NMR and combustion analysis are consistent with those values predicted for the desired product. Combustion Analysis for C33H56N2O6S--Calculated: C, 65.1%; H, 9.3%; N, 4.6%; S, 5.3%. Found: C, 65.6%; H, 9.1; N, 4.4%; S, 5.0%.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17]([CH:19]=[CH2:20])=O.S(=O)(=O)(O)O.N1CCCCC1>[Cl-].[Al+3].[Cl-].[Cl-].C(O)(=O)C>[C:13]([C:12]1[C:7]2[C:8](=[CH:17][CH:19]=[CH:20][CH:6]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:15])[C:14]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: C=CC=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cccc2ccccc12

Procedure:
It has been known to produce benzanthrone by the following processes. (1) Anthraquinone is dissolved into sulfuric acid and a mixture of metallic powder and glycerin is added to the solution to reduce anthraquinone and simultaneously, the reaction product is further reacted with the compound resulted by dehydration of glycerin in an addition-reaction (B10S 987 and F1AT 1313). (2) Benzanthrone is produced by reacting an anthrahydroquinone ester such as acetate and sulfate which is obtained by reducing and esterifying anthraquinone, with acrolein in the presence of a dehydration catalyst such as sulfuric acid and piperidine in a solvent of acetic acid. (DRP 720,467). (3) Benzanthrone is produced by condensing α-benzoylnaphthalene at higher than 150° C. in the presence of aluminum chloride catalyst or at 120° C. in the presence of iron chloride catalyst. (DRP 239,761).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:23][C@@H:24]1[CH2:28][CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:25]1
Reactant: C[C@@H]1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: C[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-3-methylpyrrolidine (1.2 equiv) to give 141 (2.4 mg, M+1 381.1)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+].Cl>C(C(C)=O)C.CCO.C(Cl)Cl>[N:34]1([CH2:33][CH2:32][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[N:9]=3)=[CH:4][CH:3]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(O)cc3)n2)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3ccc(OC)cc3)c(-c3ccc(OCCN4CCCC4)cc3)n2)cc1
Yield: 62.4 %

Procedure:
The 2-(4-hydroxyphenyl)-3,6-bis(4-methoxyphenyl)pyridine (2.3 g, 6 mmol), N-(2-chloroethyl)pyrrolidine hydrochloride (1.1 g, 6 mmol), and powdered K2CO3 (4.1 g, 30 mmol) were stirred in 250 mL methyl ethyl ketone and refluxed 18 h. The TLC (EtOH/ CH2Cl2, 1:4) of the reaction mixture indicated some starting material remained, so more N-(2-chloroethyl)pyrrolidine hydrochloride (0.3 g, 1.6 mmol) and K2 CO3 (2 g, 15 mmol) were added and reaction mixture refluxed an additional 18 h. The reaction mixture was worked up, concentrated, and the residue was dissolved in 25 mL MeOH, treated with 5 mL HCl/ MeOH at 0° C., and concentrated. The residue was recrystallised from MeOH/ Et2O to give 1.8 g (58% yield) of product as the HCl salt: mp 230°-231° C.; 1H NMR (CDCl3) d 1.61 (bs, 2H, pyrrolidine), 2.10-2.26 (comp, 4H, pyrrolidine), 2.90-3.10 (bs, 2H, pyrrolidine), 3.48 (bs, 2H, NCH2), 3.84 (s, 3H, ArOCH3), 3.88 (s, 3H, ArOCH3), 4.10-4.14 (m, 2H, OCH2), 6.78-6.81 (d, 2H, J=9 Hz, ArH), 6.86-6.89 (d, 2H, J=9 Hz, ArH), 7.00-7.03 (d, 2H, J=9 Hz, ArH), 7.14-7.16 (d, 2H, J=9 Hz, ArH), 7.44-7.46 (d, 2H, J=9 Hz, ArH), 7.66-7.73 (m, 2H, ArH), 8.07-8.10 (d, 2H, J=9 Hz, ArH); MS(FD) 480(M+). Anal. Calcd for C31H32N2O3HCl: C, 72.01; H, 6.43; N, 5.42. Found: C, 72.02; H, 6.65; N, 5.24.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[Na+].Cl>O.C(OCC)(=O)C.CN(C)C=O>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: BrCCOC1CCCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(OCCOC3CCCCO3)cc2)OC1(C)C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Into dimethylformamide (250 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (10.0 g, 45.5 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (10.0 g, 45.5 mmol) were dissolved, to which 60% sodium hydride in oil (2.98 g, 68.3 mmol) was added while cooling with ice, followed by stirring for three hours while cooling with ice, and further for 17 hours at room temperature. Ethyl acetate was then added, and excess hydrated sodium was neutralized with 1M hydrochloric acid. Further, water was added and the resulting solution was separated. The resulting organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-70:30, V/V) to give the desired title compound (13.3 g, yield 84%).
Reaction SMILES: [NH2:1][C@@:2]([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])([CH3:6])[CH2:3][CH2:4][OH:5].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[C:31]([N:39]=[C:40]=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:31]([NH:39][C:40]([NH:1][C@@:2]([C:7]1[CH:12]=[C:11]([Br:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])([CH3:6])[CH2:3][CH2:4][OH:5])=[S:41])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@](N)(CCO)c1cc(Br)c(F)cc1F
Reactant: O=C(N=C=S)c1ccccc1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: C1CCOC1
Product: C[C@@](CCO)(NC(=S)NC(=O)c1ccccc1)c1cc(Br)c(F)cc1F
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of (S)-3-amino-3-(5-bromo-2,4-difluoro-phenyl)-butan-1-ol (9.5 g, 34 mmoles, 1 equiv) in THF (50 mL) is added bis(trimethylsilyl)trifluoroacetamide (8.7 g, 34 mmol, 1 equiv). After 2 h, benzoyl isothiocyanate (5.5 g, 34 mmoles, 1 equiv) is added dropwise. The reaction is stirred 18 h, quenched with water, and extracted with ethyl acetate. The combined organic phases are extracted with 1 N HCl and saturated aqueous NaCl. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (>95% yield, 90% purity as determined by LCMS): MS (m/z): 443, 445 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=1.CO>O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:19]2[N:18]=[C:17]3[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)=[N:16]3)=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1)c1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Yield: 31.5 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 4-trifluoromethylbenzoic acid (2.7 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(4-fluorophenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (2.1 g) is dissolved in boiling methanol (50 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with methanol (3×5 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Fluorophenyl)-1,8-naphthyridin-2-yl]-4-trifluoromethylbenzamide (1.3 g), m.p. 198° C., is obtained.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[C:6]([N+:13]([O-:15])=[O:14])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])#[N:4].O1CCCC1>C(O)C>[OH:9][CH2:8][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([CH:12]=[CH:11][CH:10]=1)[C:3]#[N:4]
Reactant: N#Cc1cccc(C=O)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cccc(CO)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of NaBH4 (0.2 g) in ethanol (10 ml) at ice bath temperature was added a solution of 3-cyano-2-nitrobenzaldehyde from Example 2c (0.93 g) in ethanol:tetrahydrofuran (15 ml:15 ml). After the addition was completed, the solution was warmed to ambient temperature and stirred for 30 minutes. The volatiles were removed under aspirator vacuum and the residue suspended in water. Dilute (1% aqueous) hydrochloric acid was added slowly until gas evolution had ceased. Ethyl acetate was then added followed by saturation of the aqueous layer with K2CO3. The layers were separated and the ethyl acetate layer was washed with brine, dried (Na2SO4) and concentrated to leave the title product (0.85 g, 90%) as a yellow solid: tlc, Rf =0.25, silica gel, ethyl acetate:hexane (1:1).