Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]1(=[O:29])[N:6]([CH2:7]CC[N+](CCCNC(OC(C)(C)C)=O)(C)C)[C:5](=[O:24])[C:4]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:3]12.[CH3:30][NH2:31]>>[CH3:30][NH:31][C:5](=[O:24])[C:4]1[C:3](=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]([NH:6][CH3:7])=[O:29]
Reactant: CC(C)(C)OC(=O)NCCC[N+](C)(C)CCCN1C(=O)c2ccccc2C1=O
Reactant: CN
Agent: [Br-]
Product: CNC(=O)c1ccccc1C(=O)NC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(phthalimidopropyl)-N-((t-butoxycarbonylamino)propyl)-N,N-dimethylammonium bromide [1.6] (4.1 g, 0.87 mmol) was dissolved in ethanolic methylamine (33 wt %, 8.02M, 10 ml). The colourless solution was stirred at room temperature for 3 days, during which time a thick white precipitate formed (N,N′-dimethylphthalamide). The mixture was filtered; the solid was washed with a little cold ethanol. The filtrate was evaporated under reduced pressure to give an oil; this was triturated with ether and dried under high vacuum to give the title compound [1.7] as a foam. Used without further purffication.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([OH:9])[CH:8]=1.[CH2:11]([O:13][C:14](=[O:25])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=1[CH3:24])[CH3:12].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:11]([O:13][C:14](=[O:25])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH3:10])=[CH:19][C:18]=1[CH3:24])[CH3:12]
Reactant: COc1ccc(C)c(O)c1
Reactant: CCOC(=O)C=Cc1ccc(F)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C=Cc1ccc(Oc2cc(OC)ccc2C)cc1C
Temperature: 140 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
The compounds of 5-methoxy-2-methyl-phenol (1.46 g, 9.60 mmol), 3-(4-fluoro-2-methyl-phenyl)-acrylic acid ethyl ester (1.00 g, 4.80 mmol), potassium carbonate (1.33 g, 9.60 mmol) are dissolved in dimethylsulfoxide (12 mL) under nitrogen, and the mixture is stirred overnight at 140° C. HCl 10% is added, and the mixture is extracted with diethyl ether. The organic layer is washed with water, dried (Na2SO4) and filtered, and then the solvent is evaporated in vacuo. Purification by flash chromatography by eluting with hexane:ethyl acetate 10:1 to afford the title compound (0.74 g, 47%). Rf=0.44 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.34 (t, 3H, J=7.3 Hz), 2.13 (s, 3H), 2.40 (s, 3H), 3.74 (s, 3H), 4.26 (q, 2H, J=7.1 Hz), 6.28 (d, 1H, J=15.9 Hz), 6.53 (d, 1H, J=2.4 Hz), 6.66-6.73 (m, 3H), 7.15 (d, 1H, J=8.3 Hz), 7.51 (d, 1H, J=8.3 Hz), 7.93 (d, 1H, J=16.0 Hz).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2ccccc2)c(=O)[nH]c1=O
Yield: 75 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (275 mg, yield: 75.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[C:7]([Br:24])[CH:6]=1.CCCCCCC.C(OCC)(=O)C.[N+:39]([O-])([OH:41])=[O:40]>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:14]=[C:15]([CH:21]([CH3:23])[CH3:22])[C:16]([O:19][CH3:20])=[C:17]([N+:39]([O-:41])=[O:40])[CH:18]=2)=[C:7]([Br:24])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c(C(C)C)c2)c(Br)c1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(OC)c([N+](=O)[O-])c2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of methyl[3,5-dibromo-4-(3-isopropyl-4-methoxyphenoxy)phenyl]acetate (1.0 g, 2.12 mmol) in benzene (150 mL), nitric acid (0.81 mL, 65%) was added drop-wise. The mixture was further stirred for 1 hour at room temperature. The reaction was monitored by TLC (65:35 n-heptane/ethyl acetate) and the reaction mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate. The resulting organic and aqueous phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, brine, and the organic phase was dried over magnesium sulfate, and concentrated. The crude product was crystallized from methanol to give 1.1 g, (99%) of methyl[3,5-dibromo-4-(5-isopropyl-4-methoxy-3-nitrophenoxy)phenyl]acetate.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:6][N:5]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N+:35]([O-:38])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])([OH:3])=O.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>>[Cl:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([S:10]([N:8]1[CH2:7][CH2:6][N:5]([C:24]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][N+:35]([O-:38])=[CH:34][CH:33]=4)=[CH:30][CH:31]=3)=[O:25])[CH:4]([C:1]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[O:3])[CH2:9]1)(=[O:12])=[O:11])[CH:22]=[CH:21]2
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1

Procedure:
In a similar manner to Example 4 except for the use of 4-[4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide and 2-(dimethylamino)ethylamine as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[N:20]=[C:19]1[NH2:35]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[N:20]=[C:19]1[NH2:35])=[NH:5]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: Nc1nc(-c2ccc(-c3ccccc3)cc2)cn1N
Agent: Cl
Solvent: CC(C)O
Product: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc(-c3ccccc3)cc2)nc1N
Temperature: 120 °C
Reaction time: 28 h

Procedure:
20 ml of concentrated hydrochloric acid are added, with stirring, to a mixture of 5.09 g (0.0248 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 6.23 g (0.0248 mol) of 1,2-diamino-4-(4-biphenylyl)-imidazole and 70 ml of isopropanol, and the mixture is stirred at 120° C. for 28 hours. Cooling to room temperature, filtration, washing the crystallizate with isopropanol and drying under a high vacuum yield the title compound with a water content of 0.9%, m.p. 284°-285° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.28 (d, 1H); 7.99 (s, 4H); 7.80 (s, 4H); 7.60-7.76 (m, 4H); 7.35-7.53 (m, 3H); 3.32 (s, 4H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[OH:20])=[CH:8][CH:7]=[N:6]2)[CH2:2]1.CO.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:25][N:1]1[CH2:2][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=3[OH:20])=[CH:8][CH:7]=[N:6]2)[CH2:4]1
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnn1C1CNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenol, (Preparation 856, 190 mg, 0.00067 mol) was stirred in dichloromethane (5 mL), methanol (0.5 mL) and acetic acid (0.1 mL). Aqueous formaldehyde (0.25 mL of 37% wt/vol, 0.00336 mol) was added and the reaction stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (711 mg, 0.00336 mol) was added and the reaction stirred at room temperature for 4 hours. The solvents were removed in vacuo and the residue dissolved in water. Aqueous ammonium hydroxide (7.5 molar) was added to pH 10 to give a white precipitate. The mixture was extracted with ethyl acetate (1×20 mL). The organic layer was separated and washed with saturated aqueous sodium chloride solution (2×10 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and the solvents removed in vacuo to give the title compound as a foam. (140 mg).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:39])[NH:29][C:30]1[CH:35]=[C:34]([CH2:36][OH:37])[CH:33]=[C:32]([CH3:38])[N:31]=1)([CH3:26])([CH3:25])[CH3:24].O>ClCCl.N1C=CC=CC=1>[C:23]([O:27][C:28](=[O:39])[NH:29][C:30]1[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[C:32]([CH3:38])[N:31]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(CO)cc(NC(=O)OC(C)(C)C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Dess-Martin periodinane (50.0 g, 0.118 mol, 1.34 eq) was portionwise added to a solution of 4 (21.0 g, 0.088 mol) in dichloromethane:pyridine 10:1 (1.1 L). The resulting solution was stirred at room temperature for 2 h and then water (700 mL) was added. The mixture was stirred for a further 5 min, and then the layers were separated. The aqueous layer was extracted with dichloromethane (1×11), the combined organic phase dried and the solvent evaporated to give a brown solid which was purified by column chromatography (EtOAc:hexane 1:2) to afford (4-formyl-6-methyl-pyridine-2-yl)-carbamic acid tert-butyl ester 5 (20.5 g, 99%) as a pale orange solid.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:19]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][NH:22][CH:21]([CH3:28])[CH2:20]3)[CH:15]=2)[N:10]=[C:9]1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([O:36][CH3:37])[CH:30]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:9]2[N:8]([CH2:7][C:6]([OH:38])=[O:5])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:19]4[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][NH:22][CH:21]([CH3:28])[CH2:20]4)[CH:15]=3)[N:10]=2)=[CH:30][C:31]=1[O:36][CH3:37]
Reactant: COc1cc(-c2nc3ccc(N4CC(C)NCC(C)(C)C4)cc3c(=O)n2CC(=O)OC(C)(C)C)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nc3ccc(N4CC(C)NCC(C)(C)C4)cc3c(=O)n2CC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[2-(4-Fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]acetic acid tert-butyl ester (INTERMEDIATE VII.12) (160 mg, 0.305 mmol) was dissolved in DCM (10 mL) and TFA (3 mL) added. The reaction mixture was stirred at room temperature overnight. Crude reaction mixture was poured directly onto an SCX cartridge, the cartridge was washed with MeOH and product eluted with 2N NH3/MeOH. Solvent was removed under reduced pressure to afford [2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]acetic acid (INTERMEDIATE IX.1) which was used without further purification.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Pt](=O)=O>[C:20]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=2)[C:8]([NH2:10])=[O:9])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)c1ccc([N+](=O)[O-])cn1
Agent: O=[Pt]=O
Solvent: CCO
Product: NC(=O)C(c1ccccc1)(c1ccccc1)c1ccc(N)cn1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A mixture of 8.86 g of diphenyl-(5-nitro-2-pyridyl)acetamide (26.5 mmol) in 50% EtOH/glacial AcOH with 100 mg platinum (IV) oxide was shaken on a Parr hydrogenator (30 psi H2) for 3 hr. The mixture was filtered through a bed of Celite, then the ethanol was evaporated under reduced pressure. The mixture was then basified with K2CO3 and extracted with EtOAc (4×), dried (MgSO4), filtered through Celite again and evaporated. The remaining solid was recrystallized from hexane/EtOAc/MeOH to furnish the title compound (7.9 g, 98%) as a tan crystal. mp 215-20° C. 1H NMR (CDCl3; 300 MHz) δ 3.85 (2H, bs, NH), 5.88 (1H, bs, CONH), 6.54 (1H, d, J=8.4 Hz), 6.84 (1H, dd, J=3 and 8.7 Hz), 7.01-7.06 (4H, m), 7.24-7.32 (6H, m), 8.11 (1H, d, J=2.4 Hz, H-6), 9.57 (1H, bs, CONH). Elemental analysis calculated for C19H17N3O.0.25H2O: C, 74.15; H, 5.69; N, 13.67. Found: C, 74.06; N, 5.69; H, 13.78.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH2:31][CH:32]=O>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH2:31][CH2:32][N:6]1[CH2:5][CH2:4][N:3]([CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[C:2](=[O:1])[CH2:7]1
Reactant: COc1cc([N+](=O)[O-])ccc1CC=O
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Product: COc1cc([N+](=O)[O-])ccc1CCN1CCN(C2CCc3cc(C#N)ccc3C2)C(=O)C1

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and (2-Methoxy-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 435 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C:7]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH2:21]([Li])CCC.CCCCCC.CI>C(OCC)(=O)C.CCCCCC.O1CCCC1>[C:17]([NH:16][C:5]1[C:4]([C:1](=[O:3])[CH2:2][CH3:21])=[C:9]([CH3:10])[CH:8]=[C:7]([NH:11][C:12]([CH3:13])([CH3:15])[CH3:14])[N:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)c1c(C)cc(NC(C)(C)C)nc1NC(C)(C)C
Reactant: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CI
Product: CCC(=O)c1c(C)cc(NC(C)(C)C)nc1NC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 2.77 g. (10 mmol.) of 3-acetyl-2,6-di-t-butylamino-4-methylpyridine (Compound V) in about 30 ml. of dry tetrahydrofuran stirred under nitrogen at 0° C., 6.2 ml. of a 1.6M solution of n-butyl lithium in hexane (10.3 mmol.) was slowly added so as to maintain the temperature below 5° C. 0.8 ml. of methyl iodide was then added and the reaction mixture was allowed to come to room temperature over a 1 hr. period. (Thin layer chromatography (25% ethyl acetate/hexane) revealed a mixture of two products (approximately 50% and 25%) and starting material (approximately 25%)). The reaction mixture was partitioned between chloroform and water, the aqueous phase was re-extracted twice with chloroform and the combined chloroform phases were dried over anhydrous sodium sulfate and evaporated at reduced pressure. Since the desired product in pure form could not be obtained from the residue by crystallization, the residue was dissolved in a minimum amount of chloroform applied to 250 ml. of silica (2.5 cm. column diameter) and eluted with 50% toluene/hexane. The fractions containing the desired (major) product were combined and stripped to dryness at reduced pressure and the residue was recrystallized from methanol/water to obtain the product as yellow crystals (1.3 g.), m.p. 102°-103° C.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][CH:5]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[NH:23]1C2C(=CC=C(C(C3C=CC=CC=3OC)CC(NC)=O)C=2)C=[CH:24]1>>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=3)[CH2:4][C:3]([NH:23][CH3:24])=[O:22])[CH:21]=2)[CH:17]=[CH:18]1
Reactant: COC(=O)CC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1
Reactant: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Product: CNC(=O)CC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1
Yield: 89 %

Procedure:
3-(1H-Indol-6-yl)-3-(3-chloro-phenyl)-N-methyl-propionamide XLI (340 mg, 89% yield) was prepared from 3-(1H-indol-6-yl)-3-(3-chloro-phenyl)-propionic acid methyl ester using the procedure described above for 3-(1H-Indol-6-yl)-3-(2-methoxy-phenyl)-N-methyl-propionamide XXXVIII (see Example 9).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[N:25]1([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][OH:40])=[CH:33][CH:32]=2)[CH:29]=[N:28][CH:27]=[N:26]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:40][CH2:39]/[CH:38]=[CH:37]/[C:34]2[CH:35]=[CH:36][C:31]([CH2:30][N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)=[CH:32][CH:33]=2)=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: OC/C=C/c1ccc(Cn2cncn2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cn3cncn3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (E)-3-{4-(1,2,4-triazol-1-yl-methyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 MM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperatures, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, the captioned compound was obtained. The yield was 522 mg (98.6%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24](Cl)=[CH:23][N:22]=1)COCC[Si](C)(C)C)(=[O:11])=[O:10].[CH2:30]([CH2:32][NH2:33])[OH:31].[H-].[Na+]>COCCOC>[NH2:33][CH2:32][CH2:30][O:31][C:24]1[N:25]=[C:26]([O:27][CH3:28])[C:21]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])=[N:22][CH:23]=1
Reactant: COc1nc(Cl)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: NCCO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1nc(OCCN)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 115a) (0.25 g) was added to a mixture of ethanolamine (0.05 mL) and sodium hydride (0.035 g of a 60% dispersion in oil) in 1,2-dimethoxyethane (15 mL) at room temperature. After 2 h, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. Chromatography on silica gel eluting with methanol/dichloromethane mixtures gave the title compound containing the SEM ([2-(trimethylsilyl)ethoxy]methyl) protecting group as an oil (0.14 g). Trifluoroacetic acid (1 mL) and dichloromethane (3 mL) were added. After 0.5 h at room temperature, toluene was added and the solution evaporated to dryness. HCl (4M in dioxane) was added and the mixture evaporated to dryness. The product was crystallised from diethyl ether (0.075 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]=2[CH:19]=[O:20])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=[O:27])[CH2:25]Br)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([O:23][C:24](=[O:27])[CH2:25][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][C:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]=2[CH:19]=[O:20])[CH2:2][CH2:3]1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1[nH]c2c(c1CCCN1CCNCC1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
3-(3-Piperazin-1-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (170 mg, 0.62 mmol), prepared as described in Example 8, was mixed with bromo-acetic acid ethyl ester (89 ml, 0.8 mmol, 1.3 eq.) and potassium carbonate (342 mg, 2.5 mmol, 4 eq.) in dimethylformamide. The mixture was stirred at room temperature overnight. The salt was filtered out and the filterate was rotary evaporated and purified by flash chromatography, eluting with (dichloromethane/methanol 40/1, 30/1) to give 140 mg of {(4-[3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid ethyl ester.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:12]=[N:13][C:14]([S:17][CH:18]3[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=1>>[CH:1]1([CH:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH:18]3[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)[C:8]([NH:21][C:22]2[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: O=C(O)/C(=C/C1CCCC1)c1ccc(SC2CC2)nc1
Product: CCOC(=O)c1cnc(NC(=O)C(=CC2CCCC2)c2ccc(SC3CC3)nc2)s1

Procedure:
(E)-3-Cyclopentyl-2-(6-cyclopropylsulfanylpyridin-3-yl)acrylic acid (Preparation 15, 250 mg, 0.86 mmol) was condensed with ethyl 2-aminothiazole-5-carboxylate (297 mg, 1.73 mmol), using the method described in EXAMPLE 12, to furnish ethyl 2-[3-cyclopentyl-2-(6-cyclopropylsulfanylpyridin-3-yl)acryloylamino]thiazole-5-carboxylate: m/z (ES+)=444.3 [M+H]+. This ester was saponified, employing a procedure similar to that described in Step 3 of Preparation 16, to give 2-[3-cyclopentyl-2-(6-cyclopropylsulfanylpyridin-3-yl)acryloylamino]thiazole-5-carboxylic acid: m/z (ES+)=416.1 [M+H]+. Oxidation of this thioether, utilising an approach similar to that described in EXAMPLE 35, afforded 2-[3-cyclopentyl-2-(6-cyclopropanesulfonylpyridin-3-yl)acryloylamino]thiazole-5-carboxylic acid: m/z (ES+)=448.2 [M+H]+. This carboxylic acid (52 mg, 116 μmol) was condensed with MeNH2.HCl in the presence of NEt3, utilising the general procedure described in EXAMPLE 12, to give the title compound: RTA=3.29 min; m/z (ES+)=461.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH2:23])=[S:22])=[CH:16][CH:15]=1)[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:25](I)[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[NH:23])[S:22][CH2:25][CH3:26])=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(NC(N)=S)cc1
Reactant: CCI
Product: CCSC(=N)Nc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)OC)cc1
Yield: 96 %

Procedure:
Using the compound obtained in Example 224 as a starting material and also using ethyl iodide as a reagent, the same procedure of Example 29 gave 0.55 g of the titled compound (yield, 96%).