Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].[NH2:12][CH2:13][CH:14]([N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1)[CH2:15][OH:16]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:12][CH2:13][CH:14]([N:17]2[CH:21]=[CH:20][C:19]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=3)=[N:18]2)[CH2:15][OH:16])=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(-c2ccn(C(CN)CO)n2)cc1Cl
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)NCC(CO)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 6.49 %

Procedure:
3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-3-hydroxypropyl)-1H-pyrazole-5-carboxamide was prepared using the method of Example 34(d) starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (84 mg, 0.542 mmol) and 4-(1-(1-amino-3-hydroxypropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (125 mg, 0.452 mmol). The product was triturated using diethyl ether and acetonitrile, respectively. Yield 6.49%. 1H-NMR (400 MHz; MeOD): δ 2.51 (s, 3H), 3.88 (m, 2H), 3.97 (dd, 1H), 4.03 (dd, 1H), 4.65 (m, 1H), 6.77 (d, 1H), 7.21 (s, 1H), 7.75 (d, 1H), 7.79 (d, 1H), 7.91 (dd, 1H), 8.05 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5](=[N:10][O:11][CH3:12])[CH2:6][C:7](=[O:9])[CH3:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH:22]([CH3:24])[CH3:23].Cl>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5](=[N:10][O:11][CH3:12])[CH:6]([C:7](=[O:9])[CH3:8])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH3:2]
Reactant: CCOC(=O)C(CC(C)=O)=NOC
Reactant: CC(C)CI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC)C(CC(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
To a solution of 2-methoxyimino-4-oxo-pentanoic acid ethyl ester (2.62 g, 14 mmol) in DMF (30 mL) is added potassium carbonate (2.5 g, 18.2 mmol) followed by 1-iodo-2-methyl-propane (1.62 mL, 14 mmol) and the mixture is stirred at ambient temperature overnight. Additional 1-iodo-2-methyl-propane (0.8 mL, 7 mmol) is added and the mixture is stirred at 60° C. for 1 hour. The reaction mixture is diluted with EtOAc and is adjusted to pH 3 with 1N HCl. The organic layer is washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified by column chromatography (0 to 20% EtOAc in hexanes) to give the title compound as a colorless oil (1 g, 29%). 1H NMR (400 MHz, CDCl3) δ 4.33 (q, 2H), 4.06 (s, 3H), 4.03 (dd, 1H), 2.07 (s, 3H), 1.88 (m, 1H), 1.58 (m, 1H), 1.43 (m, 1H), 1.37 (t, 3H), 0.89 (d, 6H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([C:11]1([CH2:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH3:10].O>CS(C)=O.C1COCC1>[CH2:9]([C:11]1([CH2:21][C:22]2([C:23]([F:24])([F:26])[F:25])[CH2:4][O:27]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH3:10]
Reactant: CCC1(CC(=O)C(F)(F)F)CCCc2ccccc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CCC1(CC2(C(F)(F)F)CO2)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (74 mg of a 60% dispersion in mineral oil, 1.85 mmol) in DMSO (5 ml) was added a solution of trimethylsulphoxonium iodide (610 mg, 2.77 mmol) in DMSO (5 ml). After stirring at room temperature for 30 min a solution of 3-(1-ethyl-1,2,3,4-tetrahydro-1-naphthalenyl)-1,1,1-trifluoro-2-propanone (Intermediate 13) (500 mg, 1.85 mmol) in THF (3 ml) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with diethylether. The organic extract was washed repeatedly with water, dried over anhydrous sodium sulphate and evaporated in vacuo to give the title compound as a crude mixture of diastereomers. Extraction of aqueous layer with dichloromethane yielded further title compound as a crude mixture of diastereomers. Combined products were then applied to a 20 g silica SPE cartridge eluting with a 0-10% dichloromethane in cyclohexane gradient for 10 min followed by 10% dichloromethane in cyclohexane for 5 min. This gave, in order of elution, Intermediate 14 (racemic diastereomer 1, 178 mg): and Intermediate 15 (racemic diastereomer 2, 86 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10]>O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([N:2]([CH3:3])[CH3:1])=[O:10]
Reactant: O=C(Cl)CCCCCl
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCCCl
Yield: 84.6 %

Procedure:
A solution of 20.0 g (0.44 mole) of dimethylamine in 100 ml of cold tetrahydrofuran (THF) was added dropwise to a solution of 20.0 g (0.13 mole) of 5-chlorovaleryl chloride in 100 ml of THF. The reaction mixture was stirred mechanically and the temperature maintained between 5° and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates, and the filtrate was concentrated under reduced pressure to yield 18.0 g (85%) of yellow oil. An analytical sample was prepared by filtering this oil through a small bed of silica gel and eluting with ethyl acetate-hexane (1:1). The fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a light-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12.[S:10](Cl)([CH3:13])(=[O:12])=[O:11].C1(=O)NC(=O)C=C1>N1C=CC=CC=1>[S:10]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12)([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1cccc2c1CC2
Agent: O=C1C=CC(=O)N1
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1cccc2c1CC2

Procedure:
4-Mesyloxybenzocyclobutene is prepared by reaction between 4-hydroxybenzocyclobutene and mesyl chloride (methanesulfonyl chloride) in pyridine, using excess pyridine as solvent. The mesyloxy compound is reacted with maleimide, otherwise as in paragraph (a), to produce 4-(N-maleimidyl)benzocyclobutene, which is hydrolyzed with hydrazine hydrate to 4-aminobenzocyclobutene, otherwise as in paragraph (b).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O

Procedure:
The product from Example 35E and 4-chlorophenylacetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.70 (s, 2H) 7.28-7.52 (m, 5H) 7.50-7.70 (m, 5H) 7.72-7.99 (m, 1H) 8.47 (dd, J=8.85, 5.49 Hz, 1H) 11.62-11.89 (m, 1H); MS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH:15]=[CH2:16])[CH3:12].C(O)(=O)C>C(#N)C>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][CH2:16][SH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH3:12]
Reactant: C=CC(OCC)OCC
Reactant: Cc1nc2ccccc2s1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(CC[SH]1C(C)=Nc2ccccc21)OCC

Procedure:
1-(3,3-Diethoxypropyl)-2-methyl-benzothiazole was prepared by reaction of 2-methylbenzothiazole (125 mg, 0.84 mmol) with acrolein diethyl acetal (1.64 g, 12.6 mmol) and acetic acid (100 μl) in acetonitrile (4 ml) by a method analogous to that described in Section 1.2. The product was purified by HPLC on a Rainin Dynamax C18, 8 μm using a 0-100% gradient elution of water/acetonitrile (containing 0.1% TFA) over 60 minutes at 20 ml/min. The product was obtained as a colourless oil (220 mg, 95%); m/z (FAB+): 280.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:4][CH2:3]1.[Cl:16][S:17](O)(=[O:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>ClCCl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[C:12]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH2:6][CH2:7]1
Reactant: COc1ccccc1N1CCN(C)CC1
Reactant: O=S(=O)(O)Cl
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
2-(4-Methylpiperazin-1-yl)anisole (200 mg, 1 mmol) was added in portions over ten minutes to ice-cooled, stirred chlorosulfonic acid (1.2 ml) under argon. The resulting brown solution was stirred at 0° C. for 0.25 h and then at ambient temperature for a further 1.25 h. The solution was slowly poured onto crushed ice (50 g). Dichloromethane (50 ml) was added to the mixture followed by saturated sodium carbonate solution until pH10 was attained in the aqueous phase. The layers were separated and the aqueous phase further extracted with dicholoromethane. The combined organic phases were dried (Na2SO4) and concentrated to an oil. The oil was stirred with hexane (4 ml) to give the title compound as a cream solid (210 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C@@H:14]([NH:16][C:17]2[N:22]=[C:21]([C:23]([O:25]C)=O)[CH:20]=[N:19][CH:18]=2)[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH3:30]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C@@H:14]([NH:16][C:17]2[N:22]=[C:21]([C:23]([NH2:30])=[O:25])[CH:20]=[N:19][CH:18]=2)[CH3:15])[CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: N
Reactant: COC(=O)c1cncc(N[C@@H](C)c2cccc(NC(=O)c3cccc(C)c3)c2)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(C(N)=O)n3)c2)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of (S)-methyl 6-(1-(3-(3-methylbenzamido)phenyl)ethylamino)pyrazine-2-carboxylate (40 mg, 0.1 mmol) and aqueous ammonia (4 mL, 28%) in dioxane (2 mL) was heated at 130° C. in a sealed tube for 18 hours. After this time the mixture was allowed to cool to room temperature and was diluted with ethyl acetate (20 mL). The two phases were separated and the aqueous phase extracted with ethyl acetate (10 mL). The combined organic solutions were washed with brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give (S)-6-(1-(3-(3-methylbenzamido)phenyl)ethylamino)pyrazine-2-carboxamide (37 mg, 98%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][C:11]=3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1.[ClH:29]>O1CCOCC1>[ClH:29].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][C:11]=3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccccc1-c1cccc2[nH]c3c(c12)CCN(C(=O)OC(C)(C)C)CC3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Temperature: 25 °C
Reaction time: 3.7 h

Procedure:
The tert-butyl 10-(2-methylphenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.53 g, 1.40 mmol) from above was treated with a solution of 4 N HCl in dioxane (10 mL) and stirred at room temperature for 3.7 hours. After the reaction mixture was concentrated in vacuo CH2Cl2 was added and the solution was concentrated in vacuo to give a green solid (475 mg) which was recrystallized from CH3OH/ethyl acetate to give 0.362 g (82%) of a light brown solid as the title compound: mp 278.5-281° C. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.40 (br s, 1H), 7.32-7.22 (m, 4H), 7.15 (d, J=7.2 Hz, 1H), 7.09-7.05 (m, 1H), 6.68 (d, J=7.1 Hz, 1H), 3.26 (m, 2H), 3.17-3.16 (m, 2H), 2.98 (m, 2H), 2.37-2.27 (m, 2H), 1.98 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 140.9, 135.8, 135.5, 134.5, 132.7, 129.4, 129.2, 127.2, 125.3, 125.0, 120.2, 119.7, 110.0, 109.7, 45.9, 44.2, 24.3, 21.1, 19.6; IR (diffuse reflectance) 3257 (s), 2992 (s), 2946 (s,b), 2906 (s,b), 2849 (s), 2831 (s), 2801 (s), 2774 (s), 2676, 2572, 2446, 1463, 1336, 766, 744 (s) cm−1; HRMS (FAB) calcd for C19H20N2+H1 277.1704, found 277.1702. Anal. Calcd for C19H20N2.HCl.0.5EtOAc: C, 72.69; H, 6.80; N, 8.83. Found: C, 72.60; H, 6.82; N, 8.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH:18]1([NH:24][C:25]([CH:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH3:28])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:32]1[CH2:33][CH2:34][N:29]([CH:27]([C:25]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:26])[CH3:28])[CH2:30][CH2:31]1)=[O:9]
Reactant: CC(C(=O)NC1CCCCC1)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NC3CCCCC3)CC2)cc(OC)c1OC
Reaction time: 0.33 h

Procedure:
0.64 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 0.50 g of 1-[1-(cyclohexylaminocarbonyl)ethyl]piperazine and 0.27 g of triethylamine in 15 ml of chloroform, and the resulting solution is kept standing at room temperature for 20 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Br:23][C:24]1[CH:25]=[C:26]([F:34])[CH:27]=[C:28]2[C:32]=1[NH:31][C:30](=[O:33])[CH2:29]2>>[Br:23][C:24]1[CH:25]=[C:26]([F:34])[CH:27]=[C:28]2[C:32]=1[NH:31][C:30](=[O:33])/[C:29]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Product: Cc1c(/C=C2\C(=O)Nc3c(Br)cc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 76.44 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b obtained from step 1 of Example 4 as starting materials to obtain (Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 56 (63 mg, yield 76.44%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH:15]=[O:16])=[CH:4][CH:3]=1>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]1[CH2:10][CH2:11][CH2:12][C:13]1=[C:14]2[CH:15]=[O:16]
Reactant: O=CC#CCCC/C=C/c1ccc(Cl)cc1
Solvent: ClCCCl
Product: O=Cc1c2c(cc3ccc(Cl)cc13)CCC2
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 83.8 %

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added enyne 5j (0.035 g, 0.15 mmol) in DCE (2.5 mL). The reaction was irradiated with stirring at 180° C. for 45 min until complete by TLC. The reaction turned golden in color. The reaction was then transferred to a vial, concentrated under reduced pressure, and dried under vacuum to yield naphthalene 6j as a golden sticky solid (0.029 g, 83%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1(/[CH:15]=[CH:16]/[S:17]([NH:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=2)(=[O:19])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][S:17](/[CH:16]=[CH:15]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:19])=[O:18])[CH:22]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.27 g, 3.88 mmol) in tetrahydrofuran (5 ml) a saturated NaHCO3 solution (3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acryloyl chloride (27a) (0.27 g, 0.77 mmol) in tetrahydrofuran (3.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.115 g, 42%) as white crystals. M.p. 171° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.38 (d, J=16.0 Hz, 1H); 7.07–7.80 (m, 12H); 9.03 (br s, 1H); 10.16 (s, 1H); 10.76 (br s, 1H). HPLC analysis on Symmetry C18 column: impurities 1% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; sample concentration 0.4 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C17H16N2O4S, %: C, 59.29; H, 4.68; N, 8.13. Found, %: C, 59.13; H, 4.70; N, 7.92.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH:17]C(C2C=CC3C(=CC=CC=3)C=2)=O)[S:15][CH:16]=1.[Br:30]CC(C1C=C(C(OC)=S)SC=1C)=O.[CH:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][C:45]=1NC(N)=S>>[BrH:30].[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:46]2[CH:45]=[CH:44][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:47]=2)[S:15][CH:16]=1
Reactant: COC(=O)c1cc(-c2csc(NC(=O)c3ccc4ccccc4c3)n2)c(SC)s1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Reactant: NC(=S)Nc1ccc2ccccc2c1
Product: Br
Product: COC(=O)c1cc(-c2csc(Nc3ccc4ccccc4c3)n2)c(SC)s1
Yield: 80 %

Procedure:
Methyl 5-methylthio-4-[2-(2-naphthoylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate hydrohromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol) was allowed react with 2-napthylthiourea (42.4 mg) as described in Example 154, step (a) to give 82.5 mg (80% yield) of methyl 5-methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 2.67 (s, 3H), 3.83 (s, 3 H), 7.31 (s, 1H), 7.50-7.67 (m, 4H), 7.93 (m, 1H), 8.15 (s, 1H), 8.31-8.35 (m, 1H), 8.46 (d, 1H, J=7.6), 10.22 (s, 1H)); Mass Spectrum (ESI) m/z calcd. for C20H16N2O2S3, 412.6 (M+H), found 413.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 559.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:15]([OH:17])=O)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:15]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1ccc2nc(C(=O)O)c(OC)nc2c1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2nc(C(=O)Nc3nnn[nH]3)c(OC)nc2c1

Procedure:
3,6-Dimethoxy-2-quinoxalinecarboxylic acid (Example 12c) (2 g) and N,N'-carbonyldiimidazole (1.4 g) in tetrahydrofuran (50 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.8 g) in dimethylformamide (5 ml) was added and the mixture was heated under reflux for a further 30 minutes. The solid that crystallised from the solution on cooling was collected and dried. It had m.p. 250°-251° (d) (59%).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:53])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40](=[O:46])[NH:41][CH:42]3[CH2:45][CH2:44][CH2:43]3)=[O:34])[N:28]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:27]=2)=[O:25])[CH2:21][NH2:22])[CH2:15][CH2:14]1)=[O:12])[CH3:9].N1C=CC=CC=1.CC(OC(C)=O)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:53])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40](=[O:46])[NH:41][CH:42]3[CH2:45][CH2:44][CH2:43]3)=[O:34])[N:28]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:27]=2)=[O:25])[CH2:21][NH:22][C:3](=[O:4])[CH3:2])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CN)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNC(C)=O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 100 mg 4-[(S)-3-amino-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 2 ml dichloromethane were added 32 μl pyridine, 1.6 mg DMAP and 16 μl Ac2O at 0° C. After 1 h stirring at this temperature the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). Yield: 35 mg MS (ES+): m/e=681.
Reaction SMILES: C(O[CH2:5][C:6]1[C:7]([O:17]CC2C=CC=CC=2)=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)(=O)C.[O:25]1[CH2:29]CC[CH2:26]1.C[OH:31]>[C].[Pd]>[OH:17][C:7]1[C:6]([CH2:5][C:26]([O:25][CH3:29])=[O:31])=[CH:10][N:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]=1
Reactant: C1CCOC1
Reactant: CO
Reactant: CC(=O)OCc1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: [Pd]
Product: COC(=O)Cc1cn(-c2ccccc2)nc1O
Reaction time: 1 h
Yield: 93 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazol-4-ylmethyl acetate (2.35 g), 5% palladium-carbon (4.00 g), tetrahydrofuran (25 ml) and methanol (25 ml) was stirred under a hydrogen atmosphere for 1 hr. Palladium-carbon was filtered off and the filtrate was concentrated to give methyl 3-hydroxy-1-phenyl-1H-pyrazol-4-ylacetate (1.58 g, yield 93%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 144–145° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[NH:24][C:23](=[O:30])[CH2:22]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=2)[NH:24][C:23]1=[O:30])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1cc2c(cc1OC)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5,6-dimethoxy-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-5,6-dimethoxy-1,3-dihydroindol-2-one as a yellow-orange solid.