Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH2:16][NH:15][CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9].Cl[C:18]1[C:19]2[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:31]=3[S:39][CH3:40])[C:20]=2[N:21]=[C:22]([CH3:24])[N:23]=1.C(=O)([O-])O.[Na+]>C(O)C>[C:8]([C:11]1[CH2:16][N:15]([C:18]2[C:19]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[CH:32][C:31]=4[S:39][CH3:40])[C:20]=3[N:21]=[C:22]([CH3:24])[N:23]=2)[CH2:14][CH2:13][CH:12]=1)(=[O:10])[NH2:9]
Reactant: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(Cl)nc(C)nc21
Reactant: NC(=O)C1=CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CSc1cc(C(C)C)ccc1-n1c(C)c(C)c2c(N3CCC=C(C(N)=O)C3)nc(C)nc21
Yield: 26.7 %

Procedure:
In 4 ml of ethanol, 0.27 g of 5-carbamoyl-1,2,3,6-tetrahydropyridine trifluoroacetate and 0.36 g of 4-chloro-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine were dissolved, and subsequently, 0.39 g of diisopiopylethylamine was added thereto. The reaction mixture was heated under reflux for 8.5 hours, and subsequently, a saturated aqueous solution of sodium hydrogencarbonate was poured therein to. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform—methanol=60:1), followed by crystallization from a mixed solvent of ethyl acetate-diethyl ether to yield 0.12 g of 4-(5-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)-7-(4-isopropyl-2-methylthiophenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:15])=[C:7]([N+:12]([O-:14])=O)[CH:8]=2)[CH2:3]1.[N:16]#[C:17][NH2:18].[CH]Cl.[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]3[N+:12]([O-:14])=[N:16][C:17]([NH2:18])=[N:15][C:6]3=[CH:5][C:4]=2[CH2:3]1
Reactant: CN1CCc2cc([N+](=O)[O-])c(N)cc2C1
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2cc3c(cc2C1)nc(N)n[n+]3[O-]
Temperature: 60 °C
Yield: 68.7 %

Procedure:
A mixture of 6-nitroaniline 255 (2.3 g, 10.7 mmol) and cyanamide (2.0 g, 46.6 mmol) was melted at 100° C. The mixture was cooled to 60° C. and cHCl (5 mL) was slowly added. The solution was heated at 100° C. for 90 min, then a further three aliquots of cyanamide (2.1 g) and cHCl (5 mL) were added over 3 h. The solution was cooled to 50° C. and made basic with NaOH solution (7.5 M, 20 mL). The solution was heated at 100° C. for another 90 min, cooled and diluted with water (50 mL). The solid was filtered and washed with water to give 1-oxide 256 (1.70 g, 66%) as a brown solid: mp 170-175° C.; 1H NMR [(CD3)2SO] δ 7.90 (s, 1H, H-10), 7.25 (s, 1H, H-5), 7.15 (br s, 2H, NH2), 3.62 (s, 2H, H-6), 2.96 (t, J=5.9 Hz, 2H, H-8), 2.62 (t, J=5.9 Hz, 2H, H-9), 2.35 (s, 3H, NCH3); 13C NMR δ 159.8, 146.8, 144.3, 132.0, 128.4, 121.9, 118.3, 57.3, 51.9, 45.4, 28.3; MS (APCI) m/z 232 (MH+, 100%). Anal. calcd for C11H13N5O.½H2O: C, 55.0; H, 5.9; N, 29.1. Found: C, 55.6; H, 5.5; N, 28.7%.
Reaction SMILES: [K].[CH3:2][C:3]1[C:4]([CH3:14])=[C:5]([CH3:13])[C:6]([Si:9](Cl)([CH3:11])[CH3:10])([CH3:8])[CH:7]=1.[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1>>[CH3:2][C:3]1[C:4]([CH3:14])=[C:5]([CH3:13])[C:6]([Si:9]([CH:15]([C:19]2[CH:8]=[CH:6][CH:7]=[CH:3][CH:2]=2)[C:16]2[CH:13]=[CH:5][CH:4]=[CH:14][CH:17]=2)([CH3:11])[CH3:10])([CH3:8])[CH:7]=1
Reactant: C1CCOC1
Reactant: CC1=CC(C)([Si](C)(C)Cl)C(C)=C1C
Agent: [K]
Product: CC1=CC(C)([Si](C)(C)C(c2ccccc2)c2ccccc2)C(C)=C1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium diphenylmethanite (4.91 g, 23.8 mmol) was slowly added to (tetramethylcyclopentadienyl)dimethylsilylchloride (5.11 g, 23.8 mmol) dissolved in about 65 mL of THF at about 25° C. A precipitate formed and the reaction mixture was stirred about 16 hours more at about 25° C. after which time the reaction mixture was filtered, the solvent was removed under reduced pressure and the residue was extracted with hexane and filtered. The solvent was removed under reduced pressure to give the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15]([CH3:20])[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)C=C)CCC.[Li+].[Cl-]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15]([CH:20]=[CH2:24])[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc2c(c1)C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1)C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Temperature: 110 °C

Procedure:
Degassed mixture of (R)-2-benzyl-8-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (50 mg, 0.13 mmol), tributyl(vinyl)tin (64 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium (9.1 mg, 0.013 mmol) and LiCl (27.5 mg, 0.65 mmol) in toluene (1 mL) was heated at 110° C. for 18 h to give dark brownish reaction mixture. The mixture was then cooled, diluted with ethyl acetate (10 mL) and filtered through bed of celite and rinsed with more ethyl acetate (20 mL). Filtrate was concentrated and purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to give (25 mg, 60%) as a faint yellow oil. MS (ESI) 319 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:13][C:14]([F:27])([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)[CH:15]([F:17])[F:16].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:13][C:14]([F:27])([O:18][C:19]1[CH:20]=[C:21]([CH2:22][NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:24]=[CH:25][CH:26]=1)[CH:15]([F:16])[F:17]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Ethyl 3-aminobenzoate (6.75 mL, 0.045 mol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (10 g, 45 mmol) were dissolved in 100 mL of dichloroethane and acetic acid (2.7 mL, 47 mmol), then solid NaBH(OAc)3 (14.3 g, 67 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and evaporated to give 16.7 g (98%) of the desired ethyl 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzoate product as a yellow oil. 1H NMR (CDCl3) δ 1.3 (t, 3H), 4.3 (q, 2H), 4.5 (s, 2H), 6.5 (tt, 1H), 6.9 (d, 1H), 7.1-7.4 (m, 7H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][CH:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[CH:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:36])=[N:4][CH:5]=1)[CH2:25][C:26]([F:28])([F:29])[F:27]
Reactant: CC(=O)O
Reactant: N#Cc1ncc(NC(CC(F)(F)F)C(N)=O)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(NC(CC(F)(F)F)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4,4,4-trifluorobutanamide (5 mg, 0.012 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (4 mg). MS 420.3 (M+H); UV 204.7, 263.3, 297.7 nm; t 0.417 min.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].Br[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>N1C=CC=CC=1.C(OCC)(=O)C.[Cu-]=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(Br)cc1
Agent: O=[Cu-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccccc2n1-c1ccc(C)cc1
Temperature: 120 °C
Yield: 100.1 %

Procedure:
2-Carboethoxy-indole (100 mg, 0.528 mmol, 1.0 eq.) was combined with 4-bromotoluene (0.16 ml, 1.32 mmol, 2.5 eq.) and copper(I) oxide (75.6 mg, 0.528 mmol, 1.0 eq.) in pyridine (0.53 ml, 1M) and heated at 120° C. for 2 hours. The reaction was then cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was washed twice with water, twice with 1N hydrochloric acid and once with aqueous saturated sodium hydrogen carbonate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluting with chloroform:hexane (1:2) to give the title A compound (147.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>N1C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: c1ccncc1
Product: Cc1ccc2nc(Oc3ccccc3)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with phenyl chloroformate (3.3 ml, 26 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 h, after which time the pyridine was removed in vacuo. The residue was washed with water (20 ml) and dried in vacuo. Recrystallisation from toluene afforded the desired product as a pale brown solid (692 mg, 41%); δH (400 MHz, DMSO-D6) 2.40 (3H, s, CH3), 7.33-7.45 (3H, m, Ph), 7.48-7.55 (3H, m, Ph), 7.63 (1H, d, J 8, Ph), 7.89 (1H, s, Ph-H5); m/z (ES+) 254 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:44]([N:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[CH2:56]O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:55][CH2:54][CH2:53][C@@H:52]1[CH2:56][N:15]1[C:14](=[O:17])[N:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]2=[N:16]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: OC[C@@H]1CCCN1Cc1ccccc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(C[C@H]2CCCN2Cc2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 10.8 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (S)-1-benzyl-2-pyrrolidinemethanol (27 mg, 0.14 mmol) in THF (1.0 mL) and by following the procedure described in Example 2. The title compound, (R)-2-((1-benzylpyrrolidin-2-yl)methyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (8 mg, 11%) was obtained as yellow powder. MS M+H=530; 1H NMR (CDCl3) δ 8.14 (1H, s), 7.22-7.38 (11H, m), 7.10 (2H, d, J=10.0 Hz), 4.61-4.63 (1H, m), 3.50-3.56 (2H, q, J=13.2 Hz), 3.01 (1H, d, J=10.0 Hz), 2.85 (1H, d, J=10.0 Hz), 2.37-2.42 (1H, t, J=10.7 Hz), 1.99-2.02 (2H, m), 1.82-1.95 (1H, m), 1.70-1.80 (2H, m).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=1[F:18])C.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][CH:5]([C:6]2[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:7]=2[F:18])[C:4]([OH:28])=[O:3])=[CH:21][CH:22]=1)#[N:27]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCC)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(OCC)c(F)c(C(Nc2ccc(C#N)cc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
The (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid ethyl ester (1.02 g) described in example 2.2 was dissolved in THF. 1 M LiOH (3.96 ml) was added and the mixture was stirred for 2 h at room temperature. 1 M HCl (4 ml) was added. The product was isolated by extraction with ethyl acetate to give 970 mg of (RS)-(4-cyano-phenylamino)-(3,5-diethoxy-2-fluoro-phenyl)-acetic acid which was used for the next step without further purification. MS: 357 ([M−H]−)
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Concentrated sulphuric acid (2 ml) was added to a stirred mixture of 3-bromophenol (67 g) and acetic anhydride (20 ml). The mixture was stirred at ambient temperature for 4 hours and evaporated. Ice was added and the mixture was extracted with diethyl ether. The organic phase was dried (MgSO4) and evaporated to give 3-bromophenyl acetate (75.4 g, 90%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:5][CH:4]=1)[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[NH2:12][C:11]1[C:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[C:13]([NH2:14])[NH:17][N:16]=1
Reactant: NN
Reactant: CCc1ccc(CC(C#N)C#N)cc1
Solvent: CCO
Solvent: O
Product: CCc1ccc(Cc2c(N)n[nH]c2N)cc1
Temperature: 25 °C

Procedure:
A mixed solution of 4-ethylbenzyl bromide (10.0 g), malononitrile (6.64 g), potassium carbonate (6.94 g) and tetra-n-butylammonium bromide (648 mg) in toluene (100 ml) was agitated at room temperature for 17 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate twice. The extract was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give 2-(4-ethylphenylmethyl)malononitrile (3.28 g) as a colorless solid. (2) A solution of the above 2-(4-ethylphenylmethyl) malononitrile (1.30 g) and hydrazine hydrate (0.86 ml) in ethanol (35 ml) was heated under reflux for 4 hours. Hydrazine hydrate (0.43 ml) was further added thereto and the mixture was further heated under reflux for 4 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-diethyl ether to give 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (2.63 g) as pale pink powder. APCI-Mass m/Z 217 (M+H). (3) The above 3,5-diamino-4-(4-ethylphenylmethyl)pyrazole (1.30 g) was added to 50% aqueous phosphoric acid solution (19 ml), and further added thereto was water (10 ml). The mixture was cooled to 0° C., and thereto was added dropwise an aqueous solution (4 ml) of sodium nitrite (912 mg). The mixture was stirred at the same temperature for 30 minutes, and further stirred at room temperature for 4 hours. The reaction mixture was cooled again to 0° C., 10% aqueous sodium hydroxide solution was added thereto to adjust pH of the reaction mixture to 7. The mixture was extracted with ethyl acetate, washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give the desired 4-(4-ethylphenylmethyl)pyrazole (414 mg) as a pale brown semisolid. APCI-Mass m/Z 187 (M+H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][C@@H:16]([OH:19])[CH2:17][CH3:18]>>[C@H:16]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:17][CH3:18])[CH3:15]
Reactant: CC[C@@H](C)O
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CC[C@@H](C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example A14(c) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) and (R)-butan-2-ol. MS (m/e): 271.1 ([M−H]−, 100%)
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cccnc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1cccnc1-c1cc(C)c(Br)c(C)c1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-3-methyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.88 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]([NH:9][CH:10]([C:11]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCC(=O)c1ccco1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccco1
Yield: 72.7 %

Procedure:
4.0 g of N-benzoyl-(2-furylcarbonyl)methylamine, 0.8 g of 61% sodium hydride and 3.2 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 4.0 g of ethyl 3-benzoylamino-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 72.7%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([CH2:16][N:17]=[C:18]=S)[CH2:15][CH2:14]1>C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:18]([NH:17][CH2:16][CH:13]3[CH2:15][CH2:14]3)=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: S=C=NCC1CC1
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: O=S1(=O)N=C(NCC2CC2)Nc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 2-amino-5-chlorobenzenesulfonamide and cyclopropylmethyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 288-290° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.20-0.54 (m, 4H, CH2CH2), 1.05 (m, 1H, CH), 3.10 (distorted t, 1H, NHCH2), 7.22 (d, 1H, ArH), 7.31 (br., 1H, NH), 7.55-7.69 (m, 2H, ArH), 10.7 (br.s, 1H, NH); MS: m/e 285/287 (M+); (C11H12N3Cl1O2S1) calc. C, 46.24; H, 4.23; N, 14.71; found C, 46.48; H, 4.32; N, 14.72.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][NH:12][CH2:11]1>O>[CH3:9][CH:10]1[CH2:15][CH:14]([CH3:16])[CH2:13][N:12]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:11]1
Reactant: Nc1cccc(F)n1
Reactant: CC1CNCC(C)C1
Solvent: O
Product: CC1CC(C)CN(c2cccc(N)n2)C1
Temperature: 205 °C
Yield: 83 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and 3,5-dimethylpiperidine (0.61 g, 5.35 mmol) in water (0.2 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200-300 mesh, ethyl acetate:petroleum ether=1:8) to afford 6-(3,5-dimethylpiperidin-1-yl)pyridin-2-amine (0.76 g, 83%) as a yellow oil. LC-MS: [M+1]+=206, tR=1.240 min.
Reaction SMILES: [Br-].[C:2]([NH:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[CH2:17]([N:14]1[CH2:15][CH2:16][C:11]([NH:10][C:2](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:12][CH2:13]1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1cc[n+](CCc2ccccc2)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NC1=CCN(CCc2ccccc2)CC1)c1ccccc1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
4-Benzamido-1-phenethylpyridinium bromide (3.0 g.) in methanol (100 ml.) was treated with sodium borohydride (6.0 g.) in portions over 30 minutes. The solution was stirred during the addition and for 1 hour after. Water was then added to the warmed solution until crystallisation commenced to give the title compound (2.15 g.), m.p. 115°-7° C. (Found: C, 78.2; H, 7.3; N, 9.1 C20H22N2O requires C, 78.4; H, 7.2; N, 9.1%).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:19][CH3:20])=[N:16][C:17]#[N:18])[N:9]=1)[C:2]([NH2:4])=[NH:3].[ClH:21].C[OH:23]>>[ClH:21].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:19][CH3:20])=[N:16][C:17](=[O:23])[NH2:18])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Reactant: CO
Agent: Cl
Product: CNC(=NC(N)=O)NCCSCc1csc(NC(=N)N)n1

Procedure:
A mixture of 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (1.0 g.), and 2.5 N hydrochloric acid (12 ml.) was heated for four minutes on the steam bath. On cooling a white solid precipitated which was applied to Merck 60 F-254 preparative thin layer chromatography plates and eluted with chloroform/methanol/ammonia (s.g. 0.880) 7:3:0.5 v/v/v. The yellow foam obtained was dissolved in methanol and methanolic hydrogen chloride added. The solution was evaporated to dryness and the residue crystallized from methanol to give 2-guanidino-4-[2-(2-carbamoyl-3-methylguanidino)ethylthiomethyl]thiazole hydrochloride, m.p. 148°-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[NH2:25])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]1=[O:37].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[NH:25][C:27]2([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])(=[O:16])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)cc2N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
The mixture of 4-(2-Amino-4-chloro-benzenesulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.051 mmol), rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (30 mg, 0.081 mmol) and K2CO3 (30 mg, 0.22 mmol) in DCM (1 mL) was stirred at room temperature overnight. The mixture was purified by column chromatography to give 22 mg rac-4-{4-Chloro-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzenesulfonylamino}-piperidine-1-carboxylic acid tert-butyl ester. MS: [M+H]+=679