Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CCOC(=O)C[C@H]1C[C@@H](CCn2c(C(C)C)cc(-c3ccccc3)c2-c2ccc(F)cc2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and ethyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[O:12]=[C:13]([C@H:15]([CH2:17][C:18]1[CH:25]=[C:23](O)[C:21](O)=[CH:20][CH:19]=1)[NH2:16])[OH:14]>>[NH2:16][C@H:15]([C:13]([OH:14])=[O:12])[CH2:17][C:18]1[CH:25]=[CH:23][CH:21]=[CH:20][CH:19]=1.[NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: NCCc1ccc(O)c(O)c1
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The formation of trinitrophenyl-1-dopamine from dopamine (and hence the formation of dopamine from dopa) was measured in a spectrophotometer using ε340 nm=12,400 M−1 cm−1. In this assay, Phe-DC formed 9.4 nmol of dopamine and Di-ADC formed 2.74 nmol of dopamine, demonstrating once again that Di-ADC is an aromatic amino acid decarboxylase.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1>>[CH:1]1([O:7][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OC1CCCCC1
Product: COc1ccc2c(OC3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from cyclohexanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-cyclohexyloxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 353(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:52][C:53]([CH2:55][C@H:56]([NH2:67])[C:57]1[NH:61][C:60]2[CH:62]=[CH:63][C:64]([Cl:66])=[CH:65][C:59]=2[N:58]=1)=[O:54])[CH:50]=[CH2:51].ClCl>O1CCCC1.ClCCl.C(O)C>[CH2:49]([O:52][C:53]([CH2:55][C@H:56]([NH:67][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:57]1[NH:61][C:60]2[CH:62]=[CH:63][C:64]([Cl:66])=[CH:65][C:59]=2[N:58]=1)=[O:54])[CH:50]=[CH2:51]
Reactant: C=CCOC(=O)C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCOC(=O)C[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and (1S)-2-allyloxycarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.43 (silica gel: dichloromethane/ethanol=9:1); C26H27ClN4O4 (494.98); mass spectrum: (M+H)+=495/497 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([C:20]([OH:22])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:44]3[CH2:48][C:47](=[O:49])[NH:46][CH2:45]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([C:20]([N:44]3[CH2:48][C:47](=[O:49])[NH:46][CH2:45]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccncc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccncc3)n2)CN1

Procedure:
9 mg (0.03 mmol) of the compound of Example 27A is reacted analogously to the synthesis of the compound of Example 1 with 4 mg (0.03 mmol) of 4-imidazolinone-hydrochloride. 4 mg (35% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].[OH-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([F:11])([F:12])[F:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OC(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (procured from Rieke Metals, UK; 5.0 grams (g), 20.5 millimoles (mmol)) in MeOH (100 mL) at 0° C. were added sodium borohydride (NaBH4; 3.33 g, 92.5 mL) and 1 Normal (N) aqueous sodium hydroxide solution (NaOH; 10 mL). The reaction mixture was warmed to 25° C. and stirred for 2 hours (h). After the reaction was deemed complete by thin layer chromatography (TLC), saturated (satd) aqueous (aq) ammonium chloride (NH4Cl) solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether (Et2O) and washed with water (H2O; 3×50 mL). The organic layer was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to afford the title compound as a liquid (4.0 g, 79%): 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 3H), 5.00 (m, 2H), 2.74 (s, 1H); ESIMS m/z 242.97 ([M−H]−).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([O:15][N+:16]([O-:18])=[O:17])[CH2:10][O:11][N+:12]([O-:14])=[O:13])(=O)C.[OH-].[Na+]>C1COCC1.CCO>[N+:12]([O-:14])([O:11][CH2:10][CH:9]([O:15][N+:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[O:13]
Reactant: CC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])OCC(CCCCO)O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a solution of 5,6-bis(nitrooxy)hexyl acetate (31.3 g, 118 mmol) in THF-EtOH (1:1, 0.492 M) at 0° C., was added a solution of sodium hydroxide (2 N, 126 mL, 251 mmol, 2.1 equiv) dropwise over 5 min. The reaction was stirred at rt for 2 h. The reaction mixture was quenched with a saturated NaHCO3 solution and extracted 3 times with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The product was purified by combi-flash 2×120 g silica gel cartridge using gradient (0-5% in 5 min, 5-55% in 30 min, 55-70% BA/Hex in 10 min) to afford the desired product (24.5 g, Yield=92%) as a pale yellowish oil. 1H NMR (500 MHz, acetone-d6): δ 5.53-5.47 (m, 1H), 5.00 (dd, 1H), 4.72 (dd, 1H), 3.55 (d, 2H), 3.50 (t, 1H), 1.88-1.80 (m, 2H), 1.58-1.51 (m, 4H).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][C:9]([NH2:12])([CH3:11])[CH3:10])[CH:6]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:33])[CH:28](OCC)O)=[CH:23][C:22]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:33])[CH2:28][NH:12][C:9]([CH3:10])([CH3:11])[CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([I:1])[N:3]=[CH:4]2)=[CH:23][C:22]=1[NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:36])=[O:37])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(O)C(O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Reactant: CC(C)(N)CCn1cnc(I)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CCn1cnc(I)c1)NCC(O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
2.1 g (7.7 mmol) of 3-(4-iodimidazol-1-yl)-1,1-dimethyl-propylamine and 3.4 g (7.7 mmol) of N-[2-benzyloxy-5-(2-ethoxy-1,2-dihydroxy-ethyl)-phenyl]-phenylsulphonamide in 25 mL ethanol were refluxed for 18 h. The reaction mixture was cooled to 0° C. and then combined with 0.3 g (7.7 mmol) sodium borohydride. The mixture was stirred for a further 3 h at ambient temperature and then combined with glacial acetic acid. The solvent was removed using the rotary evaporator and the residue was dissolved in 300 mL ethyl acetate/water (1:2). The aqueous phase was made alkaline with conc. ammonia and separated from the organic phase. The organic phase was washed twice with 100 mL water and once with 100 mL of saturated aqueous sodium chloride solution, dried over sodium sulphate and freed from solvent using the rotary evaporator. The residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 3.5 g (5.0 mmol, 69%) N-(2-benzyloxy-5-{1-hydroxy-2-[3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethyl}-phenyl)-phenylsulphonamide were obtained as a yellowish solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3]1=[O:11].[C:12](Cl)(=[O:14])[CH3:13]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:12]([C:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[N:2]([CH3:1])[C:7]=1[CH3:8])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CC(=O)c1c(C)n(C)c(=O)n(C)c1=O

Procedure:
A mixture of Step 1 intermediate (10.0 g, 62.893 mmol), acetyl chloride (4.47 ml, 62.893 mmol) and anhydrous zinc chloride (8.57 g, 62.893 mmol) in dry benzene (150 ml) was refluxed for 48 h. The solvent was completely evaporated under reduced pressure, diluted with water (500 ml) and extracted with chloroform (3×150 ml). The combined organic layers were washed with water (150 ml), dried (Na2SO4) and concentrated. The residue obtained was purified by silica gel column chromatography by using 30% ethyl acetate in petroleum ether to afford 4.7 g of the product as a pale yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 2.55 (s, 3H), 3.37 (s, 3H), 3.48 (s, 3H).
Reaction SMILES: I[CH2:2][CH3:3].[C:4]([O:8][C:9](=[O:23])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH2:12]1)([CH3:7])([CH3:6])[CH3:5]>>[C:4]([O:8][C:9](=[O:23])[NH:10][C@@H:11]1[C:17](=[O:18])[N:16]([CH2:2][CH3:3])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH2:12]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Reactant: CCI
Product: CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21

Procedure:
In an analogous manner to that described in example 5d), the alkylation by iodoethane of (S)-(8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester [Chem.Pharm.Bull. 1986, 34(3), 1128–47] yielded (87% of theory) the title compound as a white solid, m.p.: 112° C., MS m/e (%): 307.1 (M+H+, 93).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15](C(OCC)=O)=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CCOC(=O)c1cnc(Nc2cc([N+](=O)[O-])ccc2C)nc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 80 °C
Yield: 80 %

Procedure:
140 g ethyl 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylate and 109 g potassium carbonate is suspended in a mixture composed by 1050 mL water and 560 mL ethanol. The mixture is refluxed for 1 hour, then 700 mL solvent are slowly distilled. Once completed the conversion, the mixture is cooled to 80° C. and it is adjusted to pH a 7 with 95 mL acetic acid. 560 mL N-methylpyrrolidone and 0.9 g CuO is added. The water present is distilled under reduced pressure, and the mixture is heated to 175-180° C. for 2 hours. Once completed the conversion, the mixture is cooled to 80-90° C., 1000 mL water and 5 g EDTA is slowly added, the mixture is stirred at room temperature, the product is filtrated and washed with water. Upon drying, 108 g of product with HPLC purity of 95% (A %) is achieved. This can be recrystallized from 10 volumes of 95:5 xylene/N-methylpyrrolidone to yield a product with 98% purity (A %) in a 80% yield.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([OH:28])[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:5])C.[CH3:41][NH2:42]>CO>[CH3:41][NH:42][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([OH:28])[CH2:24][N:25]([CH3:26])[CH3:27])=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:5]
Reactant: CN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(OCC(O)CN(C)C)cc3)ncc2c1=O
Solvent: CO
Product: CNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(OCC(O)CN(C)C)cc3)ncc2c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 2(c), 8 mg) in 1 mL of methanol was added 1 mL of methylamine (40 wt. % in water). The solution was stirred at 70° C. for 30 minutes. The solvent was evaporated to yield a yellow solid (6.6 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.64 (m, 1H), 9.35 (s, 1H), 8.82 (s, 1H), 7.39 (m, 2H), 7.27 (m, 1H), 7.15 (m, 2H), 6.66 (br, 2H), 4.06 (m, 1H), 3.93 (m, 2H), 3.02 (m, 5H), 2.89 (m, 4H), 2.56 (dd, 1H), 2.35 (m, 7H), 2.22 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H32N6O4: 529.25 (M+H), Found: 529.2.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].C(O)(=O)C.[BrH:20].Br.[NH+]1C=CC=CC=1>O>[Br:20][CH2:2][C:1]([C:4]1[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3]
Reactant: CCOC(=O)c1nc(NC)sc1C(C)=O
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc(NC)sc1C(=O)CBr
Reaction time: 2.5 h

Procedure:
To a mixture of ethyl 5-acetyl-2-methylamino-4-thiazolecarboxylate (7.1 g), 30% acetic acid solution of hydrogen bromide (10 ml) and acetic acid (50 ml) was added pyridinium hydrobromide perbromide (9.9 g) at ambient temperature and stirred for 2.5 hours. The reaction mixture was poured into water (300 ml) and the precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and water and the resultant mixture was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The organic extracted was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with ethyl ether to give ethyl 5-(2-bromoacetyl)-2-methylamino-4-thiazolecarboxylate (6.6 g). mp 130°-131.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][O:27][CH3:28]>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1
Reactant: COCCNCCOC
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Product: COCCN(CCOC)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and bis(2-methoxyethyl)amine (Aldrich), the title compound was obtained as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][C:18]=1[NH:25][C:26](=[O:44])[CH2:27][CH:28]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]2[O:40][CH2:41][CH2:42][O:43][C:35]=12)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O.O>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:19][C:18]=1[NH:25][C:26](=[O:44])[CH2:27][CH:28]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]2[O:40][CH2:41][CH2:42][O:43][C:35]=12)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCC(CC(=O)Nc1cc(CBr)ccc1C(C)(C)C)c1cccc2c1OCCO2
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(CC(=O)Nc1cc(CN2C(=O)c3ccccc3C2=O)ccc1C(C)(C)C)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
138 mg (0.745 mmol) of potassium phthalimide were added to a solution of 288 mg (0.573 mmol) of N-[2-t-butyl-5-bromomethyl-phenyl]-3-(2,3-ethylenedioxyphenyl)octanamide (prepared as described in Preparation 70E) in 5 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 295 mg (yield 91%) of the title compound as a colorless foam-like substance.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH:23]=O.N1CCCCC1>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:23][C:15]1[NH:14][C:22]2[C:17]([CH:16]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:3])[CH3:2]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of 5-acetyl-2-oxindole (88 mg), indole-2-carbaldehyde (87 mg) and piperidine (4 mg) in ethanol (2 mL) was held in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid which formed was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 133 mg (88% yield) of 5-acetyl-3-(1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one as an orange solid.
Reaction SMILES: I[CH2:2][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:2][C:3]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1(CI)CCCN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CNCc2ccc(OC)cc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 145 °C
Yield: 20.3 %

Procedure:
1-tert-butyl 3-ethyl 3-(iodomethyl)piperidine-1,3-dicarboxylate (C1) (4.13 mmol, 1.64 g) was dissolved in THF (5 mL), (4-methoxyphenyl)methanamine (6.19 mmol, 0.81 mL) and cesium carbonate (6.19 mmol, 2.02 g) were added and the mixture was heated for 8 h at 145° C. in the microwave. The mixture was filtered over a PE-filter and concentrated in vacuo. The crude was purified by flash chromatography (heptane/EtOAc: 0 to 45% yielding the title compound (C2) (340 mg, 20%). 1H NMR (400 MHz, DMSO, 300K): δ=1.23 (3H, t, J=7.2 Hz), 1.43 (9H, s), 1.55 (2H, m), 1.67 (1H, m), 1.89 (1H, m), 2.64 (1H, d, J=11.9 Hz), 2.77 (1H, d, J=11.9 Hz), 3.21 (1H, m), 3.51 (2H, m), 3.62 (1H, m), 3.70 (2H, m), 3.79 (3H, s), 4.14 (2H, q, J=7.2 Hz), 6.84 (2H, d, J=8.6 Hz), 7.20 (2H, d, J=8.6 Hz).
Reaction SMILES: C12N([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[N:29]=[C:30]([CH3:40])[S:31][C:32]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])=[O:27])[CH2:20]2.ClC1C=NC2C(=CC=CC=2)N=1>>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]1[S:31][C:30]([CH3:40])=[N:29][C:28]=1[C:26]([N:21]1[CH2:22][CH:23]2[CH:19]([CH2:25][N:24]2[C:9]2[CH:18]=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:20]1)=[O:27]
Reactant: Cc1nc(C(=O)N2CC3CNC3C2)c(-c2ccccc2F)s1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Clc1cnc2ccccc2n1
Product: Cc1nc(C(=O)N2CC3CN(c4cnc5ccccc5n4)C3C2)c(-c2ccccc2F)s1

Procedure:
The compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 21 and 2-chloro-quinoxaline as staring materials. (ESI) mass calcd. for C24H20FN5OS, 445.52; m/z found, 446.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:41][CH:42]([F:52])[N:43]1[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:44]1>O1CCCC1.C(=O)([O-])O.[Na+]>[F:52][CH:42]([F:41])[N:43]1[CH:47]=[C:46]([S:48]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:50])=[O:49])[CH:45]=[N:44]1
Reactant: O=S(=O)(Cl)c1cnn(C(F)F)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cnn(C(F)F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 80 mg) at room temperature, and the mixture was stirred for 10 min. 15-Crown-5 (442 mg) was added. Then 1-(difluoromethyl)-1H-pyrazole-4-sulfonyl chloride (181 mg) was added and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 380 mg, 75%).