Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:48])[N:22]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([O:32][C:33](=[O:47])[NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:28][CH2:27]3)[CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C>CO>[C:36]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][C:33]([O:32][CH:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][N:22]([CH3:23])[C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)=[CH:16][CH:17]=2)=[O:48])[CH2:27][CH2:28]1)=[O:47]
Reactant: CCOC(=O)C1CCN(Cc2ccc(C(=O)N(C)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)c1ccc(CN2CCC(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a 200 mL flask was added 1N NaOH (40 mL), MeOH (40 mL) and 1-[4-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)benzyl]piperidine-4-carboxylic acid ethyl ester (1.12 g, 1.7 mmol; prepared as described in Preparation 6). The reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure and this mixture was acidified with 1N HCl (40 mL) at 0-5° C. with an ice bath. The product was then extracted with DCM (2×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (0.80 g, 1.28 mmol) in 75% yield. The title compound was sufficiently pure to use without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23]C#C)[C:20]#[CH:21]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:21]#[C:20][CH2:19][O:22][CH3:23])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: C#CCOCC#C
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: COCC#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2

Procedure:
7 g (19.9 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 3 hours with 2.5 ml (29 mmol) of propargyl ether, 100 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 30 mg of copper(I) iodide in 70 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-(3-methoxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 146°-147°.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=[S:23])[NH2:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].[CH2:26](N)[CH2:27][CH3:28].S>C(O)C>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=[S:23])[NH:22][CH2:26][CH2:27][CH3:28])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:25]
Reactant: CCCN
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 100 °C

Procedure:
A solution of 10-(1-diethylamino-2-propyl)-2-phenothiazinecarbothioamide acid fumarate, L series (0.56 g) and propylamine (1.4 cc) in absolute ethanol (10 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil is purified by chromatography on a column (height: 25 cm; diameter: 1 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (150 cc) of ethyl acetate and cyclohexane and collecting 15-cc fractions. The combined fractions 4 to 7 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-(1-Diethylamino-2-propyl)-N-propyl-2-phenothiazinecarbothioamide, L series (0.5 g) is thereby obtained in the form of a yellow oil. 0.25 g of this product is dissolved in isopropyl ether (25 cc) and a 0.3N solution (2.2 cc) of hydrochloric acid in isopropyl ether is added dropwise, with stirring and at a temperature in the region of 5° C. Stirring is maintained for 1 hour at a temperature in the region of 5° C. The precipitate is drained, washed with isopropyl ether (3×5 cc) and dried under reduced pressure (5 mm Hg; 4 kPa) at 40° C. 10-(1-Diethylamino-2-propyl)-N-propyl-2-phenothiazinecarbothioamide hydrochloride, L series (0.24 g) is thereby obtained in the form of a yellow solid, m.p. 95°-100 C. (melts forming a paste), the NMR characteristics of which are identical to those of the product described in Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.[NH2:60][CH2:61][C:62]1[CH:63]=[N:64][CH:65]=[CH:66][CH:67]=1>O.C(N(CC)CC)C>[N:64]1[CH:65]=[CH:66][CH:67]=[C:62]([CH2:61][NH:60][C:25](=[O:26])[CH2:24][CH:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH:63]=1
Reactant: NCc1cccnc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)O)c1nnc(C)n1-2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)NCc1cccnc1)c1nnc(C)n1-2
Yield: 16.3 %

Procedure:
(±)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (1.0 g) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.2 g) are added to dimethylformamide (20 ml), and the mixture is stirred. 3-(Aminomethyl)pyridine (0.30 g) and triethylamine (0.38 g) are added, and the mixture is stirred at room temperature for 6 hours. After the completion of the reaction, water (200 ml) is added and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate and isopropyl ether, and recrystallized from ethanol to give 200 mg of (±)-N-(3-pyridylmethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide 1/2 1759 hydrate as white powdery crystals, melting point 180°-183° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](I)=[CH:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:14].[K].[C:38]1([N:44]2[C:48]([SH:49])=[N:47][N:46]=[N:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C)C=O>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:49][C:48]2[N:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:45]=[N:46][N:47]=2)=[CH:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:14]
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(I)c2ccccc2c1O
Agent: [K]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2ccccc2)c2ccccc2c1O
Temperature: 90 °C
Yield: 90 %

Procedure:
1-hydroxy-4-iodo-2'-tetradecyloxy-2-naphthanilide (9 g) and 1-phenyl-5-mercapto-tetrazole potassium salt (3 g) were solubilized im dimethylformamide (25 ml). The solution was heated at 90° C. for 1 hour under stirring. After adding ethanol (25 ml), a white solid precipitated. The solid collected by filtration was crystallized from ethanol. The yield was 90% of 1-hydroxy-4-(1-phenyl-5-tetrazolylthio)-2'-tetradecyloxy-2-naphthanilide of formula ##STR11##
Reaction SMILES: C(OC([CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[N:19][N:20]([C:22]3[CH:23]=[CH:24][C:25]4[N:26]([CH:28]=[N:29][N:30]=4)[N:27]=3)[CH:21]=2)[CH:14]=[CH:13][N:12]=1)=O)(C)(C)C.C(OC(NC1C=C(C2C(C3C=CC(F)=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C>>[CH2:9]([NH:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[N:19][N:20]([C:22]3[CH:23]=[CH:24][C:25]4[N:26]([CH:28]=[N:29][N:30]=4)[N:27]=3)[CH:21]=2)[CH:14]=[CH:13][N:12]=1)[CH3:8]
Reactant: CC(C)(C)OC(=O)CCNc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Agent: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Product: CCNc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Yield: 78.1 %

Procedure:
The reaction was carried out in the same manner as in Example 8-2) except for using 659 mg (1.32 mmol) of 4-{2-[(t-butoxycarbonyl)ethylamino]pyridin-4-yl}-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 14-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole to obtain 413 mg of the title compound as a beige powder. (Yield: 78%)
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[NH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1.O>COCCOCCOC>[CH3:23][C:16]([N:14]1[CH:15]=[C:11]([NH:10][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:12]=[N:13]1)([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CSc1nccc(=O)[nH]1
Reactant: CCOC(=O)C(C)(C)n1cc(N)cn1
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)C(C)(C)n1cc(Nc2nccc(=O)[nH]2)cn1
Temperature: 140 °C
Reaction time: 7 h
Yield: 91.2 %

Procedure:
To a solution of 2-(methylsulfanyl)pyrimidin-4(3H)-one (9.1 g) obtained in Step A of Example 347 in diglyme (60 mL) was added ethyl 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropanoate (13 g) obtained in Step B of Example 347, and the mixture was stirred at 140° C. for 7 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (17 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[O:31])[O:25][C:24]2=[O:38])=[CH:19][CH:18]=1)=[O:15])[CH2:10][CH2:11]SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].C[S+](C)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:37][C:34]1[S:33][C:32]([C:30]([NH:29][CH2:28][C@@H:26]2[O:25][C:24](=[O:38])[N:23]([C:20]3[CH:21]=[CH:22][C:17]([N:16]4[CH2:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:14]4=[O:15])=[CH:18][CH:19]=3)[CH2:27]2)=[O:31])=[CH:36][CH:35]=1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Agent: C[S+](C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2)C1=O
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
170 mg (0.292 mmol) of N2-(tert-butoxycarbonyl)-N1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-D-methionineamide are dissolved in 2 ml of DMSO and admixed with 178.5 mg (0.875 mmol) of trimethylsulphonium iodide and 60.4 mg (0.437 mmol) of potassium carbonate, and the mixture is stirred at 80° C. for 3.5 hours. The mixture is then concentrated under high vacuum and the residue is washed with ethanol. 99 mg of the target compound remain.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:14]/[N+:11]([O-:13])=[O:12])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a cool (0° C.), stirred solution of 4-anisaldehyde (1.75 mL, 14.3 mmol), nitromethane (2.0 mL, 36.9 mmol) in MeOH (6.0 mL) was added NaOH (1M, 40 mL), and allowed to warm to room temperature. After 2.5 hours, ice water was added with stirring, extracted with DCM (3×), the combined extracts were dried (MgSO4), filtered, concentrated and purified on Biotage Horizon to provide the product as a solid: 1H NMR (400 MHz, CDCl3) δ ppm: 7.97 (1H, d, J=13.64 Hz), 7.51 (1H, d, J=13.64 Hz), 7.50 (1H, d, J=8.84 Hz), 6.95 (2H, d, J=8.84 Hz), 3.86 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][C:18](OCC)=[N:17][CH2:16][CH2:15]1)=[O:13].[F:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:25]=1[C:26]([NH:28][NH2:29])=O>C(O)CCC>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:15][CH2:16][N:17]2[C:26]([C:25]3[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:24]=3[F:23])=[N:28][N:29]=[C:18]2[CH2:19]1)=[O:13]
Reactant: CCOC1=NCCN(C(=O)c2cccc(C(F)(F)F)c2Cl)C1
Reactant: NNC(=O)c1ccc(F)cc1F
Solvent: CCCCO
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccc(F)cc2F)C1
Temperature: 25 °C

Procedure:
A mixture of 1-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.167 g, 0.5 mmol, e.g. see preparation below) and 2,4-difluorobenzohydrazide (0.086 g, 0.500 mmol, CAS [118737-62-5], commercially available e.g. from Matrix Scientific or ABCR) in 1-butanol (1 ml) was heated at reflux for 1 hour. After cooling to room temperature the solvent was evaporated and the residue was purified by mass-directed automated (preparative) HPLC (MDAP). The residue was triturated with diethyl ether/isohexane and the solid was collected and dried to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(2,4-difluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.032 g) as a white solid. The solid was dried at 50° C. under high vacuum for 1 day.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:27](Cl)(=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)(Cl)Cl>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=2[N:8]=[C:44]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CCOC(=O)c1ccc(NCCCN(C)C)c(N)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)OCC)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Triethylamine (1.05 ml) was added to a solution containing ethyl 3-amino-4-{[3-(dimethylamino)propyl]amino}benzoate (1.83 g) in chloroform (20 ml), and then stearoyl chloride (2.07 g) was added thereto while being cooled with ice. After being stirred for 4 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (5.00 ml) was added to a solution containing the residue (3.95 g) in ethanol (30 ml). After being stirred for 3 hours at 90° C., the reaction mixture was neutralized with 5N sodium hydroxide aqueous solution (12 ml) and concentrated. The residue, with ethyl acetate added thereto, was washed with water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (3.28 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=20:1-10:1), thereby yielding the entitled compound (2.99 g) as orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[NH:7][C:6]2=O.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([CH3:15])[N:7]=1
Reactant: COc1cc2nc(C)[nH]c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2nc(C)nc(Cl)c2cc1OC
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A mixture of 6,7-dimethoxy-2-methylquinazolin-4(3H)-one (1.0 mg) and phosphorous oxychloride (20 mL) was refluxed for 3 h. The reaction mixture was attained to rt and poured into ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined CHCl3 layer was washed water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as a yellow color solid (1.0 g, 92%), mp 182-184° C. 1H NMR (400 MHz, CDCl3): δ 7.36 (1H, s), 7.30 (1H, s), 4.06 (6H, s), 2.81 (3H, s); LC-MS (positive ion mode): m/z 239, 241 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:35][CH2:34]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Fc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2F)CC1
Temperature: 20 °C
Yield: 46.2 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), triethylamine (3.5 cc) and 4-(2-fluorophenyl)piperazine (4.4 g) in toluene (150 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (15 cc), 2-{3-[4-(2-fluorophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole 1,1dioxide (4.8 g) is obtained, m.p. 112° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:35]([N:37]([CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34])[CH3:36]
Reactant: CCNCC
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), diethylamine (29 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (27 mg, yield 41%).
Reaction SMILES: [CH2:1]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl(O)(=O)(=O)=O>[Pd].C(O)(=O)C>[CH2:1]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]([OH:32])=[O:31])[CH:27]=2)[NH:22]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCC1Cc2cc(C(=O)O)ccc2N1

Procedure:
A mixture containing 2-(n-eicosyl)indole-5-carboxylic acid (12.8 g), 5% w/w palladium on charcoal (2.0 g), 72% w/v aqueous perchloric acid (10 ml) and glacial acetic acid (150 ml) was heated by steam whilst shaken under hydrogen. Afterwards the mixture was filtered hot through diatomaceous earth, the residue was washed with hot glacial acetic acid (400 ml), and the combined filtrates were concentrated in vacuo to about 100 ml. The residue was poured into a mixture of ice and water, 50% w/v aqueous sodium hydroxide was added to pH 12 and acetic acid was then added to pH 4-5. The product was collected and recrystallised from methanol to give (RS)-2-(n-eicosyl)indoline-5-carboxylic acid hemimethanolate (4.8 g) as a pale brown solid. m.p. 110°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][O:7][CH3:8])=[O:5].[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25](I)[C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1>>[CH3:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[C:25]([NH:1][C:2]3[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=3[C:4]([NH:6][O:7][CH3:8])=[O:5])[C:24]([C:28]([F:30])([F:29])[F:31])=[CH:23][N:22]=2)[C:17]([CH3:32])=[N:16]1
Reactant: CONC(=O)c1ccc(F)cc1N
Reactant: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Product: CONC(=O)c1ccc(F)cc1Nc1cc(Nc2cn(C)nc2C)ncc1C(F)(F)F
Yield: 39.3 %

Procedure:
2-amino-4-fluoro-N-methoxybenzamide (90 mg, 0.49 mmol) and N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (110 mg, 0.29 mmol) were reacted according to the procedure of example 14.01. After chromatography, the solvent was evaporated to dryness, the residue triturated in tBuOMe and the resulting precipitate was collected by filtration and dried to a constant weight to afford the title compound (50 mg, 39.6%) as a white solid. NMR Spectrum: (DMSO-d6) 2.08 (s, 3H), 3.70 (s, 3H), 3.71 (s, 3H), 6.71 (bs, 1H), 6.93 (ddd, 1H), 7.36 (dd, 1H), 7.66 (dd, 1H), 7.87 (s, 1H), 8.24 (1, 1H), 8.52 (s, 1H), 9.99 (bs, 1H), 11.95 (s, 1H); Mass spectrum: MH+ 439