Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]3[CH:13]=[C:12]([CH3:14])[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:24]=[O:25]>>[CH:24]([C:13]1[N:8]2[C:9]([S:10][C:6]3[CH:5]=[C:4]([O:3][CH3:2])[CH:16]=[CH:15][C:7]=32)=[N:11][C:12]=1[CH3:14])=[O:25]
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)sc1nc(C)cn12
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)sc1nc(C)c(C=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 ml of n-butanol was dissolved 5.0 g of 2-amino-6-methoxybenzothiazole. With heating at 100° C., 25.0 g of propargyl bromide was dropwise added to the solution over 2 hours. The mixture was heated for a further 2 hours. After completion of the reaction, the solvent was evaporated to dryness. After the residue was crystallized with acetone, the crystals were recrystallized from isopropyl alcohol to give 25.1 g of 2-imino-6-methoxy-3-propargylbenzothiazole hydrobromide. The hydrobromide, 24.0 g, was added to sodium ethoxideethanol solution(Na, 2.0 g) followed by refluxing for 1.5 hours. After the reaction mixture was evaporated to dryness, water and ethyl acetate were added to the residue followed by separation. The residue obtained from the ethyl acetate phase was dissolved in ethanol and reacted with hydrochloric acid to convert the same into the hydrochloride. Recrystallization from 95% ethanol gave 17.3 g of 7-methoxy-2-methylimidazo[2,1-b]benzothiazole hydrochloride. The hydrochloride, 17.0 g, was added to a mixture of 10 ml of phosphorus oxychloride and 180 ml of dry dimethylformamide. After stirring at room temperature for one hour, the mixture was heated at 60° C. for 7 hours. The reaction solution was evaporated to dryness and the residue was dissolved in water. The solution was alkalized with potassium carbonate and extracted with chloroform. From the chloroform phase, 14.2 g of 3-formyl-7-methoxy-2-methylimidazo[2,1-b]benzothiazole was obtained. The obtained formyl compound, 3.7 g, was suspended in methanol and treated with 1.0 g of sodium borohydride. The reaction mixture was evaporated to dryness, and the obtained residue was recrystallized from ethanol to give 3.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:16](Cl)(=[O:18])[CH3:17]>>[C:16]([C:8]1[CH:7]=[C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(C)c1ccc(OC)cc1
Reactant: CC(=O)Cl
Product: CCOC(=O)C(C)c1ccc(OC)c(C(C)=O)c1

Procedure:
This compound is prepared by a Friedel-Crafts reaction between ethyl 2-(4-methoxy-phenyl)propionate and acetyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]([F:19])=[C:4]([F:20])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:22]>C1COCC1.CO>[CH3:22][O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[CH:3][C:4]([F:20])=[C:5]([F:19])[C:6]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=C(O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3.18 g, 8.77 mmol) in THF-MeOH (16 mL/5 mL) was added TMSCHN2 (5.30 mL, 10.6 mmol, 2 M solution in hexanes) at room temperature. The resulting mixture was stirred for 1 hour, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (3.31 g, 100%) that was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].CO[C:17]([C:19]1[C:27]2C(=CC=CC=2)NN=1)=O>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH:19]([CH3:27])[CH3:17])[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2cc(Br)ccc12
Reactant: COC(=O)c1n[nH]c2ccccc12
Product: COC(=O)c1nn(C(C)C)c2cc(Br)ccc12

Procedure:
The title compound is prepared essentially as described in procedure 1d WO2005/080389 substituting 6-Bromo-1H-indazole-3-carboxylic acid methyl ester for 1H-indazole-3-carboxylic acid methyl ester. ES/MS m/e 296.0 (M+1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([OH:27])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[C:29]1([C:35]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:43][CH2:42][C@@H:41]([F:44])[C@@H:40]3[C@H:36]2[CH2:37][NH:38][CH2:39]3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.C(N(CC)CC)C>[C:45]1([C:35]2([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:43][CH2:42][C@@H:41]([F:44])[C@@H:40]3[C@H:36]2[CH2:37][N:38]([C:25](=[O:27])[CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:39]3)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1N1CCCC1)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h

Procedure:
0.28 cm3 of triethylamine and 0.32 g of carbonyldiimidazole are added to a solution, cooled to 4° C., of 0.57 g of the hydrobromide salt of (2-pyrrolidinophenyl)acetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine, is added. The reaction mixture is stirred at room temperature for 24 hours and then diluted with 100 cm3 of dichloromethane, washed twice with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 38 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting fractions of 20 cm3. Fractions 26 to 54 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from an acetonitrile and diisopropyl oxide mixture (25/75 by volume). 0.16 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[(2-pyrrolidinophenyl)acetyl]perhydroisoindole is obtained in the form of white crystals; melting point 170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].[H-].[Na+]>CN(C=O)C>[CH3:24][O:23][C:21]([C:20]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]=1[NH2:16])=[O:22]
Reactant: COC(=O)CBr
Reactant: COc1ccc(CNc2ccncc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c2cnccc2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A cooled (0° C.) solution of 4-(4-methoxybenzylamino)-3-cyanopyridine (800 mg, 3.34 mmol) and methyl bromoacetate (0.37 mL, 4.02 mmol) in DMF was treated with sodium hydride (60% w/w in oil, 161 mg, 4.02 mmol) portionwise over 15 minutes. The mixture was allowed to warm to ambient temperature and stirred for 15 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (10 mL) and the solvent evaporated. The resultant residue was partitioned between EtOAc (100 mL), water (50 mL) and saturated NaHCO3 solution (5 mL). The organic phase was dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography (Si-PPC, DCM:MeOH, gradient 100:0 to 85:15) to provide the title compound as an off white solid (401 mg, 39%). LCMS (method B): RT=1.33 min, M+H+=312.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2csc(N)n2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
A mixture of 0.5 g of 4-(4-methoxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.37 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted twice with 40 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 30 ml of 50% ethanol yielded 0.24 g of N-[4-(4-methoxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as beige crystals.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20]Cl>CO>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]([O:18][CH3:20])=[O:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: ClCCl
Solvent: CO
Product: COC(=O)c1onc(-c2ccccc2)c1C(F)(F)F
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 0.500 g, 1.94 mmol) in dichloromethane (5 mL) and methanol (1 mL) at room temperature was added trimethyldiazomethane (2.0 M in ether) (1.26 mL, 2.53 mmol) slowly over 5 min. The resulting reaction mixture was stirred for 30 min. The reaction mixture was diluted with dichloromethane (40 mL) and washed with brine (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded methyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (0.513 g, 1.89 mmol, 97% yield) as a yellow oil. The product had an HPLC ret. time=2.55 min. (condition A); LC/MS M+1=272.0; 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 3H), 7.47-7.56 (m, 3H), and 7.59 (d, J=7.04 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21]CC(O)=O.[C:26]([OH:35])(=[O:34])[C:27]1[C:28](=[CH:30][CH:31]=[CH:32][CH:33]=1)S>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:15])=[CH:4][C:3]=1[S:21][C:33]1[CH:32]=[CH:31][CH:30]=[CH:28][C:27]=1[C:26]([OH:35])=[O:34]
Reactant: O=C(O)c1ccccc1S
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=C(O)c1ccccc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O

Procedure:
5.2.54 2-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)benzoic acid (14l) was prepared according to the procedure of procedure B for 10a except using thiosalicylic acid, which afforded the title compound 19 mg (99%) as a white solid, m.p.: 215° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([NH:26][C:27]2[N:28]=[C:29]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[S:30][CH:31]=2)=[O:25])[N:18]=1)C(=O)OC(C)(C)C)[CH2:4][CH:5]([CH3:7])[CH3:6].Cl.[OH-].[Na+]>CO>[OH:1][CH2:2][CH:3]([NH:8][CH2:16][C:17]1[N:18]=[C:19]([NH:23][C:24]([NH:26][C:27]2[N:28]=[C:29]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[S:30][CH:31]=2)=[O:25])[CH:20]=[CH:21][CH:22]=1)[CH2:4][CH:5]([CH3:6])[CH3:7]
Reactant: CC(C)CC(CO)N(Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(CO)NCc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Temperature: 40 °C

Procedure:
tert-Butyl (1-hydroxymethyl-3-methyl-butyl)-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-carbamate (165 mg, 0.313 mmol, Example 62) in MeOH (5 mL) was treated with HCl (0.16 mL, 0.627 mmol, 4M in dioxane). The resulting stirred solution was heated at 40° C. in a closed system for 15 h. After cooling to RT, the pH was adjusted to 7 using 1 N NaOH. Solvent was removed and the residue was extracted with CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4, and concentrated to yield a brown liquid crude product. This crude product was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave the final compound as a tan solid. MS m/z: 427.2 (M+H). Calc'd. for C21H26N6O2S-426.54.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@H:10]1[CH3:29])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][C@@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=2)[C@H:10]1[CH3:29]
Reactant: C[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1[C@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 4-[(6S,7R)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-(trifluoromethyl)benzonitrile (670 mg) in tetrahydrofuran (12 mL)-methanol (6 mL) was added 6 mol/L hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless solid (yield: 381.9 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]([C:15]2[S:19][C:18]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[O:14])[N:11]=[C:10]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:9]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O.Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:10]2[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:12]([C:13]([C:15]3[S:19][C:18]([C:20]4[CH:27]=[CH:26][C:23]([CH2:24][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:22][CH:21]=4)=[CH:17][CH:16]=3)=[O:14])[N:11]=2)[CH:29]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(-c2ccc(C(=O)N3N=C(c4cccnc4)CC3c3ccccc3O)s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(-c2ccc(CN3CCCC3)cc2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.1 %

Procedure:
To a solution of 4-(5-{[5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)benzaldehyde (0.205 g, 0.452 mmol) in THF (72 mL) was added pyrrolidine (0.042 mL, 0.50 mmol) and sodium triacetoxyborohydride (0.105 g, 0.497 mmol). The reaction mixture was allowed to stir at rt for 3 days. The solution was diluted with water and 1N aqueous HCl and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 2-[3-pyridin-3-yl-1-({5-[4-(pyrrolidin-1-ylmethyl)phenyl]-2-thienyl}carbonyl)-4,5-dihydro-1H-pyrazol-5-yl]phenol (I-56) (0.060 g, 0.118 mmol) as a white solid. LCMS: (FA) ES+ 509.4. 1H NMR (400 MHz, d6-DMSO) δ: 10.76-10.86 (bs, 1H), 9.74-9.82 (bs, 1H), 9.11 (s, 1H), 8.71-8.77 (m, 1H), 8.36-8.42 (m, 1H), 8.03-8.08 (m, 1H), 7.84-7.90 (m, 2H), 7.62-7.73 (m, 2H), 7.08 (t, 1H), 6.92-6.97 (m, 1H), 6.82-6.88 (m, 1H), 6.72 (t, 1H), 5.82-5.89 (m, 1H), 4.34-4.39 (m, 2H), 3.86-3.98 (m, 1H), 3.31-3.41 (m, 2H), 3.18-3.25 (m, 1H), 3.00-3.12 (m, 2H), 1.96-2.07 (m, 2H), and 1.82-1.94 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:27]=1[C:28]#[N:29]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:32]=[N:33][C:26]([O:25][CH3:24])=[C:27]([CH:30]=5)[C:28]#[N:29])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1C#N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 2.60 min (Method A); M+H=426 MS-ES)
Reaction SMILES: [CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:20]1(CCCS)[CH:25]=CC=C[CH:21]=1>>[CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][C:3]1[CH:25]=[CH:20][CH:21]=[CH:5][CH:4]=1
Reactant: CCCCCSc1c[nH]nc1C1CN2CCC1CC2
Reactant: SCCCc1ccccc1
Product: c1ccc(CCSc2c[nH]nc2C2CN3CCC2CC3)cc1
Yield: 11 %

Procedure:
Compound 49G was prepared following the procedure as described for the synthesis of compound 49B (see Scheme 10) using 3-phenyl-1-propanethiol as reagent. Subsequent purification by flash chromatography (EtOH) afforded compound 49G.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.[Br:13]Br>C(OCC)(=O)C>[Br:13][CH:4]1[CH2:3][CH:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12]
Reactant: CC1CCC(=O)c2ccccc21
Reactant: BrBr
Solvent: CCOC(C)=O
Product: CC1CC(Br)C(=O)c2ccccc21

Procedure:
4.8 g (0.03 mole) of 4-methyl-1-tetralone are reacted with 4.8 g (0.03 mole) of bromine in ethyl acetate, analogously to the instructions indicated in Example 29 (a), to give 2-bromo-4-methyl-1-tetralone. The oily product is further processed immediately without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)CC>[CH2:32]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:2][CH2:3]1)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CN2CCNCC2)c2ccccc21
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CC=Cc3ccccc3)CC2)c2ccccc21

Procedure:
5.05 gm of 5,11-dihydro-11-[(1-piperazinyl)acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one, 1.6 gm of sodium carbonate and 3.7 gm of cinnamyl bromide were refluxed in 80 ml of n-propanol for 3.5 hours. After evaporation, the residue was dissolved in chloroform/water. The organic phase was dried with sodium sulfate, the chloroform was distilled off, and the residue was purified on a silica gel column. After recrystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].CO[C:17](=N)[C:18]([Cl:21])([Cl:20])[Cl:19]>C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:19][C:18]([Cl:21])([Cl:20])[C:17]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(S(=O)(=O)CCO)cc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=S(=O)(CCO)c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg (2.31 mmol) 3,4-diamino-benzene-sulfonylethan-2-ol were dissolved in 10 mL concentrated acetic acid. 0.4 mL (1.4 equiv.) methyl-2,2,2-trichloroacetimidate were added slowly and the resulting mixture was stirred at room temperature for 4 h. The mixture was diluted with 100 mL toluene and the solvent was removed under reduced pressure. The residue was rinsed with toluene, filtered and dried under vacuo to give a brown crystalline solid pure enough for all further reactions. Yield: 680 mg MS (ES+): m/e=345, chloro pattern.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:11][CH2:10]1)=[O:8].[H][H]>C1COCC1.CO.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([N:9]1[CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[O:33])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:13][CH2:14]1)=[O:8]
Reactant: [H][H]
Reactant: Cn1cccc1C(=O)N1CCN(C(=O)NC2CCN(c3ccc(C=CC(=O)N4CCOCC4)cc3)CC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cccc1C(=O)N1CCN(C(=O)NC2CCN(c3ccc(CCC(=O)N4CCOCC4)cc3)CC2)CC1

Procedure:
The 4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-morpholino-3-oxopropen-1-yl)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (100 mg, 0.19 mmol) obtained in Example 11 was dissolved in THF (20 ml) and methanol (5 ml), and 10% Pd—C (39 mg) was added thereto, followed by stirring in a hydrogen atmosphere for 12 hours. After the insoluble material was filtered with Celite, the filtrate was evaporated under reduced pressure, thereby obtaining 4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-morpholino-3-oxopropyl)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (84 mg, 84%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(F)cc1)OCc1ccccc1
Reaction time: 3 h
Yield: 43.7 %

Procedure:
Benzylchloroformate (12.2 g, 72 mmol) was added dropwise to a stirred solution, at 0° C., of 4-fluorophenylethyl amine (9.42 g, 72 mmol) in 50 mL of DMF. The mixture was stirred for an additional 3 hours at the same temperature. The reaction was quenched with water and extracted with 3×100 mL of ethyl acetate. The combined ethyl acetate extracts were washed with 2×100 mL of 5% HCl, water and dried, over Na2SO4. Evaporation of the solvent resulted in a yellowish solid which was purified by recrystallization from ethyl acetate-hexane to furnish 8.6 g (46% yield) of N-Benzyloxycarbonyl-2-(para-fluorophenyl)ethylamine. mp 51°-52° C.