Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][NH:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:35])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(NCCNC(=O)OC(C)(C)C)n3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccnc(NCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of {6-[2-(2-tert-butoxycarbonylamino-ethylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.35 g, 0.72 mmol) in THF (5 mL) was treated with lithium hydroxide (0.084 g, 3.60 mmol) in water (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour then at room temperature for 1 hour. The mixture was quenched with 2N HCl to pH 2 then concentrated to approximately half of the entire volume. The mixture was diluted with brine and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated to give {6-[2-(2-tert-butoxycarbonylamino-ethylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid, as a light yellow solid (0.18 g) after lyophilization. The aqueous layer was lyophilized, diluted with water (3 mL) and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated to a light yellow solid after lyophilization, to give a total of 0.21 g (64%) of product. 1H NMR (400 MHz, CD3OD) δ8.13 (d, J=6.64 Hz, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 6.46 (m, 1H), 5.67 (dd, J=8.21, 2.40 Hz, 1H), 3.17 (dd, J=15.63, 3.13 Hz, 1H), 3.20-3.00 (m, 3H), 2.38 (br s, 4H), 1.40 (br s, 10H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:33][CH3:34])[CH:4]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]([CH3:32])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:33]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([N:24]([CH3:32])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:20][CH:21]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:34]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl 3-{[(4-{[2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}phenyl)carbonyl](methyl)amino}propanoate (253 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (225 mg, 95%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])=[C:11]2[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CC(O)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH:21]1([C:19]([C:12]2[C:13]([CH3:18])=[N:14][C:15]3[C:10]([C:11]=2[C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[CH:9][C:8]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:17][CH:16]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Temperature: 110 °C
Yield: 52.5 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg) and cesium carbonate (110 mg, 0.33 mmol). [6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-cyclopropyl-methanone [example 50] (100 mg, 0.22 mmol) in t-BuOH (5 ml) was added, followed by morpholine (24 mg, 0.27 mmol). The tube was sealed and heated at 110° C. for 6 hrs. The reaction mixture was cooled to 20° C., diluted with heptane, and filtered through Celite and purified directly by flash chromatography on silica gel in heptane/AcOEt 80:20 to give a yellow solid (52 mg, 51%). MS: m/z=451 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12]([N:19](CC=C)CC=C)[C:11]=2[NH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C>O>[CH2:1]([N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12]([NH2:19])[C:11]=2[NH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN(CC=C)c1nc(C)c(C)c2c1[nH]c(=O)n2Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: Cc1nc(N)c2[nH]c(=O)n(Cc3ccccc3)c2c1C
Temperature: 25 °C
Yield: 28.7 %

Procedure:
1-Benzyl-4-diallylamino-6,7-dimethyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (358 mg, 1 mmol) was taken up in water (10 mL) and acetonitrile (25 mL) and RhCl(PPh3)3 (286 mg, 0.3 mmol) was added in one portion and the mixture then heated at reflux for 16 h. The mixture was allowed to cool to room temperature, and then concentrated in vacuo, and the residue purified by column chromatography on silica gel using a gradient of 95:5→85:15 DCM:MeOH to afford the title compound as a pale brown solid (77 mg, 29%).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28]O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3=[CH:39][CH:38]=[CH:37][CH:36]=[C:32]3[C:33]2=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1(CCN2C(=O)c3ccccc3C2=O)CCCCC1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 66.8 %

Procedure:
2-[1-[2-(tert-Butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol (1.23 g), phthalimide (530 mg) and triphenylphosphine (1.10 g) were dissolved in tetrahydrofuran (15 mL) and stirred for 20 minutes. Diethyl azocarboxylate (0.57 mL) was then added to the solution, and it was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by chromatography (silica gel, 15-20% ethyl acetate:hexane) to give the title compound (1.08 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[C:17]([O:22][CH2:23]Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>CC(C)=O>[C:17]([O:22][CH2:23][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccc(O)cc1F
Reactant: CCCC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(=O)OCOc1ccc(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a 500 mL dry round bottom flask a were added 2-fluoro-4-hydroxybenzaldehyde (5.60 g, 40 mmol), anhydrous K2CO3 (10.6 g, 76.9 mmol) and acetone (200 mL). The mixture was stirred at room temperature for 30 minutes. To another 500 mL dry round bottom flash b were added chloromethyl butyrate (9.33 g, 61.5 mmol), KI (14.2 g, 66.6 mmol) and acetone (150 mL). This mixture was also stirred at room temperature for 30 minutes. After the solid settled down on the glassware bottom, the top yellow acetone solution in flask b was decanted into the stirring solution in the round bottom flask a. The resulting mixture was refluxed for 4 hours. Most acetone was rotary evaporated, and the residual solid was triturated with methyl tert-butyl ether (MTBE) three times (100 mL, 50 mL, 50 mL). The MTBE extract was concentrated, and the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give (3-fluoro-4-formylphenoxy)methyl butyrate (6.40 g) as a colorless oil. Yield: 43%. 1H NMR (CDCl3, 300 MHz): δ=10.18 (s, 1H), 7.80 (t, J=8.7 Hz, 1H), 6.93-6.89 (m, 1H), 6.82 (dd, J=12.3, 2.1 Hz, 1H), 5.83 (s, 2H), 2.36 (t, J=7.5 Hz, 2H), 1.64 (sextet, J=7.5 Hz, 2H), 0.92 (t, J=7.5 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=185.5 (d, J=6.1 Hz), 169.7 (d, J=258.8 Hz), 162.8 (d, J=12.2 Hz), 130.2 (d, J=3.7 Hz), 119.1 (d, J=8.5 Hz), 112.4 (d, J=3.1 Hz), 103.5 (d, J=24.4 Hz), 84.1, 35.7, 18.0, 13.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[C:15](Cl)(=[O:17])[CH3:16]>C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[C:15]([N:11]1[CH2:12][CH:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)([CH2:14]2)[CH2:10]1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(C23CC2CN(C(C)=O)C3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 1-(p-methoxyphenyl)-3-azabicyclo[3.1.0]hexane in benzene and aqueous sodium carbonate is added acetyl chloride and the mixture is stirred at ambient temperature for 18 hours. Benzene is removed by evaporation under reduced pressure, and filtration of the residual mixture gives 3-acetyl-1-(p-methoxyphenyl)-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:15]1[C:16]2[N:17]([N:21]=[C:22]([Cl:24])[N:23]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:24][C:22]1[N:23]=[C:16]2[C:15]([NH:1][C:2]3[C:3]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:19]=[CH:18][N:17]2[N:21]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CN(c1ncccc1N)S(C)(=O)=O
Product: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
N-(3-Amino-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-methyl-N-(3-nitro-pyridin-2-yl)-methanesulfonamide (6.20 g, 26.8 mmol)(prepared as described in J. Med. Chem., 2007, 50, 3431) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and Hydrogen (50 psi) in 2:1 ethyl acetate:methanol (150 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as brown solid (5.15 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.85 (dd, J=3.7, 2.5 Hz, 1H), 7.10-7.08 (m, 2H), 4.24 (br s, 2H), 3.23 (s, 3H), 3.08 (s, 3H). MS=202 (MH)+. 111b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide was prepared from N-(3-amino-pyridin-2-yl)-N-methyl-methanesulfonamide (238.0 mg, 1.183 mmol) and 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (250.0 mg, 1.075 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.185 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18-8.15 (m, 1H), 8.11 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.32-7.25 (m, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 3.31 (s, 3H), 3.07 (s, 3H). MS=353, 355 (MH)+. 111c) N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:19][NH2:20])=[O:18]>C(O)CCC>[NH2:8][C:6]1[N:7]=[C:2]([NH:20][NH:19][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:18])[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=1
Reactant: NNC(=O)c1ccco1
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Solvent: CCCCO
Product: Nc1nc(NNC(=O)c2ccco2)c2cc[nH]c2n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.5 g, 2 96 mmol) and 2-furoic acid hydrazide (0.76 g, 6.0 mmol) are taken into 30 mL of n-butanol. The mixture is stirred at 120° C. under N2 for 2 h. The solvent is evaporated in vacuum and the residue is triturated with water and filtered to afford compound N′-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbohydrazide: LC/MS (M+1=259.32). This material is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:33]=[N:32][C:31]([OH:34])=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:15][CH2:16][N:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[CH:30][C:31](=[O:34])[N:32]([CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])[N:33]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:18][CH2:19]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: COCCOCCBr
Reactant: O=C(c1ccc(-c2ccc(O)nn2)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCn1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)cc2)ccc1=O
Yield: 34.8 %

Procedure:
6-[4-({4-[(5-Chloro-1H-indol-2-yl)sulphonyl]piperazin-1-yl}carbonyl)phenyl]-pyridazin-3-ol (see WO 99/57113, 0.054 gram, 0.11 mmol), 0.016 gram of anhydrous potassium carbonate (0.11 mmol, 1.0 eq.) and 0.02 gram of 1-bromo-2-(2-methoxy-ethoxy)ethane (0.11 mmol, 1.0 eq.) were mixed in 1.5 mL of dry N,N-dimethylform-amide. The mixture was treated with microwave at 150° C. for 1 hour. Without any work-up, purification was performed on preparative HPLC, which gave 0.023 gram of 6-{4-[4-(5-chloro-1H-indole-2-sulphonyl)-piperazine-1-carbonyl]-phenyl}-2-[2-(2-methoxy-ethoxy)-ethyl]-2H-pyridazin-3-one (yield 36%).
Reaction SMILES: [CH:1](=[C:3]1[C:12](=[S:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[O:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH:1](=[C:3]1[C:12](=[S:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[O+:5]([O-:29])[CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=C1C(=S)c2cc(C)ccc2OC1c1ccccc1
Solvent: ClCCl
Product: CC=C1C(=S)c2cc(C)ccc2[O+]([O-])C1c1ccccc1

Procedure:
A cooled solution of 0.28 g 3-ethylidene-6-methyl-thioflavanone and 0.2 g meta-chloroperbenzoic acid in 3 ml methylene chloride is stirred at 0° C. for 5 minutes. After filtration the organic phase is washed with saturated sodium bicarbonate aqueous solution, then with water, dried over magnesium sulfate and evaporated. The crude solid is crystallized in cyclohexane. Pure 3-ethylidene-6-methyl-thioflavanone-1-oxide is obtained as yellow crystals; m.p. 151°-160° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=2)[C:5]([CH3:19])([CH3:18])[CH2:4][CH2:3]1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:9]([Br:21])[CH:10]=2)[C:5]([CH3:19])([CH3:18])[CH2:4][CH2:3]1
Reactant: CCCCCCc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
10 g of 1,1,4,4-tetramethyl-6-hexyl-1,2,3,4-tetrahydro-naphthalene were dissolved in 100 ml of carbon tetrachloride and, after the addition of a spatula tip of iron powder, treated dropwise at 0° C. with 6.4 g of bromine. After stirring at 0° C. for 3 hours the reaction mixture was poured into ice-water, extracted with ether and, after drying over sodium sulphate, evaporated. The crude product was purified by filtration over a silica gel column (eluent hexane/ethyl acetate=9:1) and gave 13 g of 1,1,4,4-tetramethyl-6-hexyl-7-bromo-1,2,3,4-tetrahydro-naphthalene as a pale yellow oil.
Reaction SMILES: BrBr.[O:3]=[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11])[CH3:5].C(=O)(O)[O-].[Na+].[Br:27]C(CCN1C(=O)C2N(C)C=NC=2N(C)C1=O)C(=O)C>CO.O>[Br:27][CH2:5][C:4](=[O:3])[CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11]
Reactant: CC(=O)C(Br)CCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC(=O)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1cnc2c1c(=O)n(CCCC(=O)CBr)c(=O)n2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4.93 Grams (0.031 moles) of bromine were added to a solution of 7.3 g (0.0276 moles) of compound (a) in 100 ml of methanol, at 10° C. After stirring for 15 hours at room temperature, the reaction mixture volume was concentrated to 30 ml under reduced pressure, then 60 ml of water, and 3 drops of conc. sulphuric acid were added. The mixture was stirred at room temperature for 4 hours, in order to hydrolyze any dimethylketals formed by reaction with methanol. After dilution with 50 ml of water, the pH of the mixture was adjusted to 8-9, by addition of a 10% sodium bicarbonate aqueous solution, the mixture was extracted with 3×50 ml of methylene chloride, washed with water, dried on anhydrous sodium sulfate, filtered and evaporated under vacuum. 8.3 Grams of compound were obtained, which, by TLC and NMR analysis, showed to be impure by the presence of the 1-(3-bromo-2-keto-5-pentyl)-3,7-dimethylxanthine regioisomer. The crude compound was directly used for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH:37][C@@H](C3C=CC=CC=3)CO)(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.C(Cl)(Cl)Cl>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(=O)(=O)N[C@H](CO)c3ccccc3)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
To (S)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-sulfonamide (prepared in Example 212) (813 mg) was added in water bath (at 20° C.) concentrated sulfuric acid (30 ml) and the resulting mixture was stirred for fifteen minutes. The mixture was cooled to 0° C. and to the reaction solution was then added water (60 ml) dropwise followed by an addition of chloroform (50 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford the same product as Example 209, (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (406 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.S([CH2:40][N+:41]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C>[C:40]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1)#[N:41]
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: N#CC1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To a solution of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (384 mg) and tosylmethyl isocyanide (430 mg) in 1,2-dimethoxyethane (4 ml) was added dropwise a solution of potassium tert-butoxide (448 mg) in a mixture of 1,2-dimethoxyethane and tert-butanol (1:1, 2 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 30 minutes. Then, it was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude product was crystallized from diethyl ether to give yellow crystals of 3-[2-(2-cyanocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.12 g).