Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[O:12]=[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc(CC(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 2.12 g of 1-[(3-nitrophenyl)acetyl]pyrrolidine obtained in stage a) below in 50 mL of methanol are added, under argon, 4.56 g of ammonium formate and 96 mg of 10% palladium-on-charcoal. The reaction mixture is stirred at room temperature for 1 hour and then filtered through Celite and concentrated under reduced pressure. The residue is taken up in water and extracted with dichloromethane. The organic phase is then washed with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 1.46 g of 3-(2-oxo-2-pyrrolidin-1-ylethyl)aniline, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[N:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>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.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncc(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of ethyl-5-bromonicotinate (30 g, 130.40 mmol), triethylamine (78 mL) and ethyl acetate (130 mL) is degassed for 15 min. Add trimethylsilylacetylene (88.46 mL, 625.92 mmol), bis(triphenylphosphine)palladium (II) dichloride (4.57 g, 6.52 mmol) and copper (I) iodide (0.25 g, 1.30 mmol) and stir at 50° C. under-nitrogen for 16 h. Cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 10:1 hexanes:ethyl acetate, to give the title compound (27.7 g, 86%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20](=[O:32])[CH2:21][CH2:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOC(C)=O.CCCCCC>ClC1C=CC=CC=1Cl>[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:25](=[CH:30][CH:29]=[C:28]([Cl:31])[CH:27]=3)[CH:24]=[C:23]3[CH2:22][CH2:21][C:20](=[O:32])[C:19]=23)=[CH:14][CH:13]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C#CC(=O)CC/C=C/c2ccc(Cl)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(-c2c3c(cc4ccc(Cl)cc24)CCC3=O)cc1
Yield: 89 %

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added compound 14a (0.057 g, 0.12 mmol) in 1,2-dichlorobenzene (2 mL). The reaction was irradiated with stirring at 225° C. for 60 min until complete by TLC (AcOEt/n-hexane 2:8). The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then AcOEt/n-hexane 2.5:8.5 to collect the pure product. The title compound was isolated as a yellow solid in an 89% yield (0.050 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:29][C:30]1[CH:31]=[C:32]([NH:36][C:37](=[O:62])[CH2:38][N:39]2[CH:43]=[C:42]([NH:44][C:45]3[C:54]4[C:49](=[CH:50][C:51]([O:55][CH2:56][C@@H:57]5[CH2:61][CH2:60][CH2:59][NH:58]5)=[CH:52][CH:53]=4)[N:48]=[CH:47][N:46]=3)[CH:41]=[N:40]2)[CH:33]=[CH:34][CH:35]=1.[Si:63]([O:70][CH2:71][CH:72]=O)([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64].[OH-].[Na+]>O1CCCC1.CO.C(O)(=O)C>[Si:63]([O:70][CH2:71][CH2:72][N:58]1[CH2:59][CH2:60][CH2:61][C@H:57]1[CH2:56][O:55][C:51]1[CH:50]=[C:49]2[C:54]([C:45]([NH:44][C:42]3[CH:41]=[N:40][N:39]([CH2:38][C:37]([NH:36][C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=4)=[O:62])[CH:43]=3)=[N:46][CH:47]=[N:48]2)=[CH:53][CH:52]=1)([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: O=C(Cn1cc(Nc2ncnc3cc(OC[C@@H]4CCCN4)ccc23)cn1)Nc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCN1CCC[C@H]1COc1ccc2c(Nc3cnn(CC(=O)Nc4cccc(F)c4)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
Sodium triacetoxyborohydride (0.11 g, 0.52 mmol) was added to a mixture of N-(3-fluorophenyl)-2-[4-({7-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-4-yl}amino)-1H-pyrazol-1-yl]acetamide bis(trifluoroacetate) (0.20 g, 0.29 mmol) and (tert-butyldimethylsilyloxy)acetaldehyde (0.10 ml, 0.52 mmol) in tetrahydrofuran (9 ml) and methanol (3 ml) containing a catalytic amount of acetic acid. The mixture was stirred at room temperature for 1 hour. A further portion of sodium triacetoxyborohydride (0.22 g, 1.04 mmol) was added and the mixture stirred at room temperature for 1 hour. A further portion of sodium triacetoxyborohydride (0.22 g, 1.04 mmol) was added and the mixture stirred at room temperature overnight. The mixture was poured into sodium hydroxide solution (1M, 50 ml) and extracted with dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulphate and then evaporated to leave a yellow film which was purified by silica gel chromatography. Elution with 5 to 10% methanol in dichloromethane gave 2-{4-[(7-{[(2S)-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyrrolidin-2-yl]methoxy}quinazolin-4-yl)amino]-1H-pyrazol-1-yl}-N-(3-fluorophenyl)acetamide (0.055 g, 31% yield): MS (+ve ESI): 620 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:16])=[C:7]([F:15])[CH:8]=2)[N:3]=1.C=CCCCC.[Mg].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.S(=O)(=O)(O)O.C(OC(C)C)(C)C>S(Cl)(Cl)=O.ClC(Cl)Cl.O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:16])=[C:7]([F:15])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: C=CCCCC
Product: CCOC(=O)CC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid (14.13 g) in thionyl chloride (29 cc) and trichloromethane (220 cc) is heated to a temperature in the region of 60° C. for 4 hours. The solution obtained is concentrated to dryness under reduced pressure (20 kPa) at approximately 60° C. The residue obtained is taken up with n-hexene (75 cc), drained and washed with the same solvent (2×60 cc). The yellow solid obtained (14.4 g) is dissolved in tetrahydrofuran (115 cc). This solution is introduced dropwise, with stirring, in the course of 35 minutes at between 5° and 10° C. into a solution (70 cc) of magnesium chelate of ethyl monomalonate in tetrahydrofuran, prepared under the conditions described below. The temperature is allowed to rise to approximately 20 C. and the mixture is stirred for a further 2 hours under these conditions. The solution obtained is introduced dropwise, with stirring, in the course of 30 minutes and at a temperature in the region of 5° C. into 0.5 N sulphuric acid (560 cc). The temperature of the suspension obtained is allowed to rise to 20° C. and the mixture is stirred for a further 1 hour and a half at this temperature. The product is extracted with ethyl acetate (3×250 cc). The combined organic extracts are washed with water (2×250 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at 50° C. The residue obtained is taken up with n-hexane (50 cc) containing isopropyl ether (20%), drained, washed with the same mixture (10 cc) and recrystallized in isopropanol (60 cc) containing n-hexane (30%). Ethyl 3-(2-chloro-6,7-difluoro-3-quinolyl)-3-oxo-propionate (11.84 g) is obtained in the form of a cream-colored solid, m.p. 107° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: Cc1cncc(N)c1
Reactant: CCOC(=O)c1nc(C)ccc1Br
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cncc(C)c1

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 3-Amino-5-methylpyridine was performed in accordance with the general method of Example 78, step 3 to yield the title compound as a light brown solid, MS (ISP): m/e=272.3 (M+H+).
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:10]([CH:9]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:19]=1[Cl:18])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: COc1ccc(OCCCCCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(OCCCCCCC(C(=O)c2ccccc2)C(=O)c2ccccc2)c(Cl)c1
Yield: 38.8 %

Procedure:
A mixture of 11.2 g (0.05 m) of dibenzoylmethane, 16.1 g (0.05 m) of 6-(2-chloro-4-methoxyphenoxy)hexyl bromide, 20.6 g (0.15 m) of milled potassium carbonate, 2.0 g of potassium iodide and 250 ml of 2-butanone was heated at reflux for 18 hours. The reaction mixture was filtered hot and concentrated to a brown oil. The latter was stirred with cold ether and seeded with a sample of the desired product having the m.p. 69°-70° C. The solid product thus obtained was collected to afford 9.0 g of 2-benzoyl-8-[2-chloro-4-methoxyphenoxy]-1-phenyl-1-octanone; MIC=3 microg/ml (herpes 2).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]([F:14])([F:13])[F:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:1])[CH3:15])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: CN(C)c1ccc(C#N)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(CN)cc1C(F)(F)F
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 4-dimethylamino-3-trifluoromethylbenzonitrile (0.35 g) in tetrahydrofuran (2 mL) is slowly added to a suspension of lithium aluminum hydride (0.1 g) in tetrahydrofuran (2 mL) at 0° C. and stirred under an atmosphere of argon for 2 hours. While at 0° C. water (0.1 mL) is slowly added followed by 5% sodium hydroxide (0.1 mL) and water (0.3 mL). The resulting gray solid is filtered and washed with tetrahydrofuran. The filtrates are collected and concentrated under reduced pressure and the resulting oil is chromatographed over silica gel (15% methanol in methylene chloride is used as the eluant) to provide the desired product as a pale orange oil (0.164 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=CC([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)=CC=2C(C)(C)CC=1)(=O)=O>C1COCC1>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:10]=[C:9]([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nccs2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3c2nccs2)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoate (Compound 67),400 mg (0.84 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) in 2 ml of THF was converted into the title compound (white solid) using a solution of 82 mg (1.26 mmol) of thiazole in 2 ml of THF, 81 mg (0.84 ml, 1.26 mmol) of n-butyllithium (1.5M solution in hexanes), 228 mg (3.36 ml, 1.68 mmol) of zinc chloride (0.5M solution in THF) and 10 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (0).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=O)=CC=1)([O-])=O.[OH-].[Li+]>C1COCC1>[OH:10][C@@:11]([C:18]1[N:19]=[N:20][N:21]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:29][C:30]([C:34]#[N:35])=[N:31]3)=[CH:26][CH:25]=2)[CH:22]=1)([C:14]([F:15])([F:17])[F:16])[CH2:12][CH3:13]
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-{1-[(2-cyano-4-phenylquinolin-7-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-(trifluoromethyl)propyl 4-nitrobenzoate (200 mg, 0.34 mmol) in THF (6 mL) was added lithium hydroxide IM (1.7 mL, 1.7 mmol). The mixture was stirred at room temperature for 1 h and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 1:9) gave the title compound. MS (+ESI): 438 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: C1CCNCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CN2CCCCC2)cc1
Yield: 90 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(piperidin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), piperidine (0.090 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.072 g (90%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]1[CH2:11][C:12]([OH:14])=O.[Cl:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH2:21])[S:19][CH:20]=1>>[Cl:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH:21][C:12](=[O:14])[CH2:11][N:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][CH:10]=[C:4]23)[S:19][CH:20]=1
Reactant: Nc1scc(Cl)c1-c1ncn[nH]1
Reactant: O=C(O)Cn1c(=O)ccn2nccc12
Product: O=C(Cn1c(=O)ccn2nccc12)Nc1scc(Cl)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid (94 mg, 0.488 mmol) and 4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (49 mg, 0.244 mmol) according to protocol A. Retention time (min)=2.161, method [7], MS (ESI) 376.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.31 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 7.76 (s, 1H), 6.85 (s, 1H), 6.27 (d, J=8.1 Hz, 1H), 5.94 (s, 1H), 4.98 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:10]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N+:5]([O-:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1C
Reactant: OO
Solvent: CC(=O)O
Product: COc1ccc[n+]([O-])c1C
Reaction time: 3 h
Yield: 60 %

Procedure:
15.3 g (0.124 mol) of 3-methoxy-2-methylpyridine are dissolved in 100 ml of glacial acetic acid, and 40 ml of 30% strength hydrogen peroxide are added in 4 portions at 80° C. in the course of 6 hours. The mixture is stirred for a further 3 hours and then concentrated in vacuo (1.5 kPa), and two 50 ml portions of acetic acid are added, the mixture being concentrated completely after each addition. Following negative detection of percompounds, the mixture is distilled in a bulb tube oven. The fraction which distils at 120° C. (1.5 Pa) is extracted by stirring in a little diethyl ether and the solid is filtered off and dried. 12 g (60% of theory) of 3-methoxy-2-methylpyridine 1-oxide are obtained in the form of colourless crystals of m.p. 72°-78° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:20][CH:21]=3)[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCN(C(C)c3ccc(N)cc3)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: Cc1ccc(N2CCN(C(C)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(4-methylphenyl)-4-[1-(4-aminophenyl)ethyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[1-[4-(p-methylphenyl)-1-piperazinyl]ethyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CC(C)=O.[Cl:14][CH2:15][C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:14][CH2:15][C:16]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Yield: 85.5 %

Procedure:
81 g (0.5 mol) of 3,4-dichloroaniline are dissolved 500 ml of acetone. 85 g (0.75 mol) of chloroacetyl chloride are poured in, over a period of 17 minutes, with stirring. The mixture is heated under reflux for 15 minutes, cooled and 350 ml of a 30% strength potassium carbonate solution in water (pH=8) are poured in. This solution is poured into a 2,000 ml Erlenmeyer flask and 500 ml of H2O+ice are added. The precipitate which appears is filtered off, washed with water, dried and recrystallised from benzene. 102 g (yield 85%) of N-chloroacetyl-3,4-dichloroaniline are thus obtained.
Reaction SMILES: CC([C@:5]1([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH2:41][N:42]3[CH:46]=[CH:45][N:44]=[CH:43]3)[CH2:35][CH2:34]2)=[O:32])[CH2:10][N:9](C2C3=NC=C(Br)C=C3CCC3C=C(Cl)C=CC2=3)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C>ClCCl>[N:42]1([CH2:41][CH2:40][CH2:39][CH:36]2[CH2:37][CH2:38][N:33]([C:31]([C@H:5]3[CH2:10][NH:9][CH2:8][CH2:7][NH:6]3)=[O:32])[CH2:34][CH2:35]2)[CH:46]=[CH:45][N:44]=[CH:43]1
Reactant: CC(C)(C)[C@]1(C(=O)N2CCC(CCCn3ccnc3)CC2)CN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CCN1C(=O)[O-]
Solvent: ClCCl
Product: O=C([C@H]1CNCCN1)N1CCC(CCCn2ccnc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-peroxybenzoic acid (25 g, 102.59 mmol, 2.5 eq.) in anhydrous dichloromethane (250 mL) was added dropwise over a period of one hour to a stirred solution of 8-chloro-4-aza-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one 1 (10 g, 41.04 mmol, 1.0 eq.) in anhydrous dichloromethane (100 mL) at 0° C. under a nitrogen atmosphere. The solution was slowly (3 h) warmed to room temperature and stirred for another 12 h. The solution was extracted with 1 M aqueous sodium hydroxide solution (5×100 mL), washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated under house vacuum at 30° C. to give 2 as a canary-yellow solid. The title compound 2 was used directly without further attempts at purification.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[N:10]([CH2:13][CH2:14][S:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH:22]=[O:23])[CH:21]=1)=[N+:11]=[N-:12]>>[N:10]([CH2:13][CH2:14][S:15][C:16]1[CH:21]=[C:20]([C:22]([C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[O:23])[CH:19]=[N:18][CH:17]=1)=[N+:11]=[N-:12]
Reactant: Ic1ncn2ccsc12
Reactant: [N-]=[N+]=NCCSc1cncc(C=O)c1
Product: [N-]=[N+]=NCCSc1cncc(C(=O)c2ncn3ccsc23)c1
Yield: 73.8 %

Procedure:
7-[5-(2-Azidoethylthio)pyridin-3-yl]carbonylimidazo[5,1-b]thiazole (667 mg) was prepared in the same manner as in step a) of Synthesis Example 3, except that 650 g of 7-iodoimidazo[5,1-b]thiazole and 570 mg of 3-(2-azidoethylthio)pyridine-5-aldehyde were used as the starting compounds.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([O:12]C)=[O:11])=[O:4].[OH-].[K+].Cl>CO.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([OH:12])=[O:11])=[O:4]
Reactant: COC(=O)C1CCCC1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1CCCC1C(=O)O
Temperature: 75 °C

Procedure:
Cyclopentane-1,2-dicarboxylic acid dimethyl ester (2.50 g, 13.4 mmol) was dissolved in methanol (2.5 mL) and a solution of potassium hydroxide (85% purity) (920 mg, 13.9 mmol) in methanol (4.0 mL) and water (0.5 mL) in a 25 mL round bottom flask. The reaction mixture was heated at 75° C. for 4 h. The reaction mixture was cooled to 0° C. and acidified to pH 2 with 2M HCl in water. The reaction mixture was diluted with water (100 mL) and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to give cyclopentane-1,2-dicarboxylic acid monomethyl ester as a faint-yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][N:8]([CH3:13])[S:9]([N:4]1[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]1)(=[O:11])=[O:10]
Reactant: Cc1cn[nH]c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnn(S(=O)(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-1H-pyrazole (10.4 g, 127.2 mmol) in CH2Cl2 (200 mL). N,N-dimethylsulfamoyl chloride (17.14 mL, 167.1 mmol) and triethylamine (35 mL, 251.1 mmol) were added to the reaction. The reaction mixture was stirred for 30 min at 0° C. in a water/ice bath and then stirred overnight at room temperature. The reaction was quenched with NaHCO3 (sat.) (40 mL) and the aqueous phase was extracted with 3×200 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/hexanes (1:6) as the eluent to afford the title compound (22.2 g, 92%) as a light yellow oil.