Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC=CC=1>[NH2:8][C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[N:23][CH:22]=2)=[CH:17][CH:16]=1)[OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(CNS(C)(=O)=O)nc3)cc2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Yield: 86.3 %

Procedure:
(4S,5R)-tert-butyl4-(fluoromethyl)-2,2-dimethyl-5-(4-(6-(methylsulfonamidomethyl)pyridin-3-yl)phenyl)oxazolidine-3-carboxylate (1800 mg, 3.64 mmol) is dissolved in dichloromethane (20 mL), and treated with trifluoroacetic acid (5.4 mL), for 4 h at room temperature. The reaction mixture is diluted with toluene (30 mL) and concentrated to a syrup. Obtained crude compound is basified with aqueous sodium bicarbonate, extracted with ethyl acetate. Extracts are dried over Na2SO4, filtered, and concentrated to give the title compound (1110 mg): m/z (CI) M+H 354.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1cc2ccn(-c3ccc(F)cc3)c2cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC#Cc1cc2ccn(-c3ccc(F)cc3)c2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 87 mg (0.28 mmol) 5-[6-Fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol in 3 ml CH2Cl2 was treated with 0.14 ml (1 mmol) NEt3 and 80 μl (0.33 mmol) MsCl, stirred at room temperature for one hour, poured into icy 0.5 M aqueous HCl and extracted three times with Et2O. Drying of the combined organic layers with Na2SO4 and evaporation of the solvent gave (93 mg) Methanesulfonic acid 5-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as a light brown oil. 31 mg of this oil were dissolved in DMF, treated with 0.2 ml Allylmethylamine and the mixture stirred at 80° C. during 2 hours. Pouring the mixture into 0.5 M NaOH, extraction with CH2Cl2, drying of the organic layers with MgSO4, and flash chromatography with CH2Cl2/MeOH 19:1 gave 24 mg (89%) Allyl-{5-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine as a light yellow oil, MS: 365 (MH+).
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].Br[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=1[Cl:24].CN(C=O)C>C(OCC)(=O)C>[Cl:21][C:20]1[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([Cl:24])[C:15]=1[CH2:14][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Yield: 81.5 %

Procedure:
Stir a mixture of potassium phthalimide (1.85 g, 10 mmol), 2-bromomethyl-1,3-dichloro-5-methoxy-benzene (2.68 g, 10 mmol) and DMF (20 mL) at 50° C. for 12 hours. Cool the reaction and dilute with ethyl acetate (60 mL) and wash with water three times and brine one time. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 1:3 ethyl acetate/hexane to afford 2.74 g (82%) of the title compound. MS (m/z): 336 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.[F:19][CH:20]([F:23])[CH2:21]I.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:15]([NH2:18])(=[O:16])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:21][CH:20]([F:23])[F:19])[CH2:11]1
Reactant: NS(=O)(=O)c1cnc(OC[C@@H]2CCNC2)c(Cl)c1
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cnc(OC[C@@H]2CCN(CC(F)F)C2)c(Cl)c1
Temperature: 25 °C

Procedure:
A reaction mixture of EXAMPLE 400B (353 mg), 1,1-difluoro-2-iodoethane (268 mg) and Na2CO3 (283 mg) in N,N-dimethylformamide (10 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Flash column purification with 2.5-3% methanol/dichloromethane provided the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([NH:27][C:28](=[O:37])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([C:18](=[O:23])C(Cl)(Cl)Cl)[C:10]=12.[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>CN(C=O)C>[N:42]1[CH:43]=[CH:44][CH:45]=[C:40]([CH2:39][NH:38][C:18]([C:17]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25]([NH:27][C:28](=[O:37])[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[O:26])=[CH:3][C:2]=3[F:1])[NH:15][CH:16]=2)=[O:23])[CH:41]=1
Reactant: NCc1cccnc1
Reactant: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc3[nH]cc(C(=O)C(Cl)(Cl)Cl)c23)c(F)c1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc3[nH]cc(C(=O)NCc4cccnc4)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1-(3-fluoro-4-(3-(2,2,2-trichloroacetyl)-1H-pyrrolo[2,3-b]pyridine 4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)urea (7.0 mg, 0.012 mmol, Example 270) in 0.5 mL of DMF was added 3-(aminomethyl)pyridine (10 mg, 0.092 mmol, Aldrich). The reaction mixture was stirred at rt for 1 h, and quenched by the addition of 1 mL of cold water. The precipitate that formed was collected by filtration, washed with cold water (1 mL) and cold acetonitrile (1 mL) and dried under vacuum to afford the desired product (4.3 mg, 64%) as a white solid. 1H NMR (DMSO-d6) δ 12.38 (s, 1H), 11.03 (s, 1H), 10.57 (s, 1H), 8.48 (s, 1H), 8.40 (t, 1H, J=5.5 Hz), 8.34 (d, 1H, J=3.3 Hz), 8.11 (d, 1H, J=5.5 Hz), 8.00 (s, 1H), 7.73 (d, 1H, J=13.2 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.37-7.29 (m, 4H), 7.16 (t, 3H, J=8.8 Hz), 6.34 (d, 1H, J=5.5 Hz), 4.48 (d, 2H, J=5.5 Hz), 3.74 (s, 2H); MS(ESI+) m/z 567.1 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[CH2:34][O:33][C:15]2([C:24]3[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][C:23]=3[O:25][CH3:26])[CH2:18][CH:17]([C:29]([O:31][CH3:32])=[O:30])[CH2:16]2)[O:14]1.[OH2:35]>O1CCCC1.CCCCCC>[CH2:34]1[CH2:13][O:14][C:15]2([C:24]3[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][C:23]=3[O:25][CH3:26])[CH2:18][C:17]([OH:35])([C:29]([O:31][CH3:32])=[O:30])[CH2:16]2)[O:33]1
Reactant: O
Reactant: COC(=O)C1Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C1(O)Cc2c(OC)ccc(OC)c2C2(C1)OCCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
(ii)(a) To a solution of 84 ml of diisopropylamine in 250 ml of dry tetrahydrofuran at -78° C. under argon were added 39 ml of a 1.6 molar solution of n-butyl lithium in hexane. The mixture was stirred for 10 minutes and then a solution of 12.32 g of methyl 4,4-ethylenedioxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate in 75 ml of dry tetrahydrofuran was added rapidly. The mixture was held at -78° C. while stirring for 50 minutes and then 27.8 g of finely ground diperoxo-oxohexamethylphosphoramidomolybdenum (VI) pyridine were added. After a further 80 minutes, the mixture was warmed to 0° C. and stirred for 20 minutes before the addition of 400 ml of water. After 10 minutes, most of the tetrahydrofuran was evaporated in vacuo and the aqueous residue was extracted with five 200 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulphate, filtered and evaporated to give an oil which was purified by chromatography on silica gel using ethyl acetate/hexane (1:1, vol/vol) for the elution. After the elution of 1.57 g of starting material, there were obtained 7.51 g (58%) of methyl rac-4,4-ethylenedioxy-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxynaphthalene-2-carboxylate in the form of colourless crystals of melting point 74°-75° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.FC(F)(F)C(O)=O.[NH2:50][C:51]1[S:52][CH:53]=[C:54]([C:56]2[CH:67]=[CH:66][C:59]([C:60]([NH:62][CH:63]3[CH2:65][CH2:64]3)=[O:61])=[CH:58][CH:57]=2)[N:55]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15](=[O:17])[NH:50][C:51]1[S:52][CH:53]=[C:54]([C:56]2[CH:57]=[CH:58][C:59]([C:60](=[O:61])[NH:62][CH:63]3[CH2:65][CH2:64]3)=[CH:66][CH:67]=2)[N:55]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-Azetidine-1,2-dicarboxylic acid 1-benzyl ester (45.7 mg, 0.19 mmol) was dissolved in DMF (1.5 mL). Triethylamine (53 μL, 0.38 mmol) and pentafluorophenyl trifluoroacetate (33 μL, 0.19 mmol) were added, and the reaction was stirred at ambient temperature for 30 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide trifluoroacetic acid salt (62.9 mg, 0. 17 mmol) was added. The reaction was stirred at ambient temperature overnight and then heated to 70° C. for 4 hours. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 7.2 mg. MS: 477.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.50-0.85 (m, 4H), 2.10-2.30 (m, 1H), 2.48-2.62 (m, 1H), 2.78-2.90 (m, 1H), 3.80-4.07 (m, 2H), 4.80-5.13 (m, 3H), 7.07-7.42 (m, 4H), 7.78-7.99 (m, 5H), 8.40-8.47 (m, 1H), 12.40-12.58 (m, 1H).
Reaction SMILES: C(OC([CH2:8][NH:9][C@H:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:11][O:12][CH2:13][C:14](O)=[O:15])=O)(C)(C)C.ON1[C:29]2[N:30]=[CH:31]C=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CNC.C(O)C>CN(C)C=O.C(OCC)(=O)C.O>[CH3:29][N:30]([CH3:31])[C:14](=[O:15])[CH2:13][O:12][CH2:11][C@H:10]([NH:9][CH3:8])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CN[C@@H](COCC(=O)O)Cc1ccccc1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CN[C@@H](COCC(=O)N(C)C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
((2R)-2-((tert-Butoxycarbonyl)methylamino)-3-phenylpropoxy)acetic acid (0.37 g, 1.14 mmol) and 1-hydroxy-7-azabenzotriazole (0.26 g, 1.14 mmol) were dissolved in N,N-dimethylformamide (7 ml). N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.37 mmol) was added. The solution was stirred for 30 min. A 33% solution of dimethylamine in ethanol (0.33 ml, 1.26 mmol) was added. The solution was stirred over night. Water (20 ml) and ethyl acetate (15 ml) were added. The organic phase was washed with a 1M solution of sodium hydrogensulfate (30 ml) and a saturated solution of sodium hydrogencarbonate (30 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (15 g) using ethyl acetate and dichloromethane (1:1) as eluent. This product was dissolved in dichloromethane (3 ml) and was cooled to 0° C. Trifluoroacetic acid (1 ml) was added. The solution was stirred at 020 C. for 20 min. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (10 ml) and 1N sodium hydroxide solution (10 ml). The phases were separated. The aqueous phase was extracted with dichloromethane (4×10 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo to give 140 mg of crude N,N-dimethyl-2-((2R)-2-methylamino-3-phenylpropoxy)acetamide, which was used for further syntheses.
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][CH:57]=2)[CH:53]([NH:58][C:59](=[O:73])[CH2:60][C:61]2[N:62]=[C:63]([C:66]4[C:71]([OH:72])=[CH:70][CH:69]=[CH:68][N:67]=4)[S:64][CH:65]=2)[C:52]3=[O:74])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[OH:72][C:71]1[C:66]([C:63]2[S:64][CH:65]=[C:61]([CH2:60][C:59]([NH:58][CH:53]3[C:52](=[O:74])[N:51]4[CH:54]3[S:55][CH2:56][CH:57]=[C:50]4[C:48]([OH:49])=[O:47])=[O:73])[N:62]=2)=[N:67][CH:68]=[CH:69][CH:70]=1
Reactant: O=C(Cc1csc(-c2ncccc2O)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCSC12
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1csc(-c2ncccc2O)n1)NC1C(=O)N2C(C(=O)O)=CCSC12
Yield: 85.5 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8k (129 mg, 0.221 mmol), Et3SiH (0.353 mL, 2.21 mmol), and trifluoroacetic acid (0.681 mL, 8.84 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9k (79.1 mg, 86%) as a yellowish solid after crystallization from THF/CH2Cl2 /hexane. mp 170° C. (dec); IR (KBr) 3600-2800 (br), 3276, 1776, 1723, 1663 cm-1 ; 1H NMR (DMSO-d6) δ3.48 (1H, dd, J=18.9 and 6.0 Hz), 3.58 (1H, dd, J=18.9 and 2.5 Hz), 3.79 (2H, s, CH2), 5.00 (1H, d, J=5.0 Hz), 5.70 (1H, dd, J=8.1 and 5.0 Hz), 6.44 (1H, dd, J=6.0 and 2.5 Hz), 7.37 (1H, dd, J=8.1 and 4.2 Hz), 7.44 (1H, d, J=8.1 Hz), 7.58 (1H, s), 8.14 (1H, d, J=4.2 Hz), 9.15 (1H, d, J=8.1Hz, NH), 11.64 (1H, s, OH), 13.20 (1H, br s, CO2H); FDMS m/z 419 (M+ +1); Anal. Calcd for C17H14N4O5S2.(C4H8O) 0.17: C, 49.30; H, 3.59; N, 13.01. Found: C, 49.13; H, 3.38; N, 12.78.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][CH2:22][O:23][CH3:24])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][CH2:22][O:23][CH3:24])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Reactant: N
Solvent: CN(C)C=O
Solvent: CO
Product: COCCc1cc(N)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.50 g (1.25 mmol) of 3-benzenesulphonyl-7-chloro-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 10:1) and crystallization from EtOH yielded 0.30 g (63%) of 3-benzenesulphonyl-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 186-187°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([O:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:10]=1)=[O:8]
Reactant: COc1cc([N+](=O)[O-])c(N)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc([N+](=O)[O-])c(N)cc1C(=O)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 5.55 g of 5-amino-2-methoxy-4-nitrobenzoic acid in 40 ml of benzene was added 40 ml of thionyl chloride, and the mixture was refluxed for 4 hours. Subsequently, an excess amount of the thionyl chloride and the solvent were evaporated, the residue was dissolved in 40 ml of benzene, and then 12.3 g of phenol and 15.3 ml of triethylamine were added under ice cooling. The mixture was stirred under ice cooling for 30 minutes and then at room temperature overnight. To the reaction solution were added water and ethyl acetate, the organic layer was washed with 10 aqueous sodium hydroxide solution and water, successively, and then the solvent was evaporated under reduced pressure. The residue was applied on a silica gel column chromatography, and the fractions eluted by benzene were collected and recrystallized from methanol to give the title compound, m.p. 130°-132° C., yield of 2.55 g.
Reaction SMILES: [OH:1][C@@H:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=3[F:26])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.C[Si]([C:33]#[CH:34])(C)C.C(N(CC)CC)C>C1COCC1.[Cu](I)I>[OH:1][C@@H:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:33]#[CH:34])=[CH:21][C:20]=3[F:26])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc2n(C)c1=O
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2c(C)c(=O)n(C)c3ncn(C[C@@H](O)CO)c(=O)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
(R)-3-(2,3 Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (200 mg, 0.4 mmol, Example 8), trimethylsilyl acetylene (66 μL, 0.6 mmol), triethylamine (84 μL, 0.6 mmol), copper iodide (14 mg, cat) and dichlorobis(triphenylphoshine) palladium(II) (14 mg, 0.02 mmol) were mixed in THF (2 mL). The mixture was subjected to microwave irradiation at 120° C. for 20 minutes. The solvent was removed in vacuo and the residue dissolved in methanol. Potassium carbonate (50 mg) was added and the solution stirred at RT for 1 hour. After filtration and evaporation the residue was purified by HPLC to give 119 mg of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.79 (s, 3H) 3.11 (s, 1H) 3.54-3.66 (m, 3H) 3.82-3.90 (m, 1H) 3.94-4.02 (m, 1H) 4.30 (dd, J=14.15, 3.79 Hz, 1H) 6.67 (t, J=8.46 Hz, 1H) 7.19 (dd, J=8.21, 0.88 Hz, 1H) 7.21-7.25 (m, 1H) 8.27 (s, 1H) [M+H] calc'd for C20H19FN4O4, 399. found, 399.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23]([NH:25][CH2:26][C:27]1([NH:32][C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:24])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[C:36]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:35]=[CH:34][C:33]([NH:32][C:27]2([CH2:26][NH:25][C:23]([NH:22][C:14]3[C:13]([CH:10]([CH3:12])[CH3:11])=[CH:18][CH:17]=[CH:16][C:15]=3[CH:19]([CH3:21])[CH3:20])=[O:24])[CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:38][CH:37]=1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(Nc2ccc(I)cc2)CCCC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(Nc2ccc(-c3ccccc3)cc2)CCCC1
Temperature: 100 °C
Reaction time: 240 h
Yield: 57.3 %

Procedure:
45 mg (0.37 mmol) of phenylboronic acid are added to 150 mg (0.29 mmol) of 1-(2,6-diisopropylphenyl)-3-[1-(4-iodophenylamino)-cyclopentylmethyl]-urea (Example 6d) in 20 ml of toluene. 370 μl (0.74 mmol) of a 2M aqueous solution of potassium carbonate are added. The reaction medium is degassed with nitrogen for 20 min, then 10 mg (8.65 μmol) of tetrakis-(triphenylphosphine)palladium are added. The medium is heated at 100° C. for 6 hours, then at ambient temperature for 10 days. It is then poured into water and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated and the residue is chromatographed on silica gel (heptane/ethyl acetate, 80/20 v/v). 78 mg of 1-[1-(biphenyl-4-ylamino)cyclopentylmethyl]-3-(2,6-diisopropyl-phenyl)-urea are obtained in the form of a white solid. (M.Pt.=198° C., Yield=57%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([C:16](=[O:27])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=O)[CH:19]=1)[CH2:7][CH2:6]2.C(Cl)(=O)C(Cl)=O.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].C(N(CC)CC)C.[OH-].[Na+]>ClCCl.CN(C)C=O.O1CCCC1.O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([C:16](=[O:27])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:26])[NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[CH:19]=1)[CH2:7][CH2:6]2
Reactant: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)O)c1)CC2
Reactant: CN(C)CCN
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)NCCN(C)C)c1)CC2
Yield: 42.5 %

Procedure:
To a suspension of 5-methylthio-6-trifluoromethyl-1-(3-carboxy phenyl carbamoyl) indoline (0.5 g, 1.26mmol) in dichloromethane (20 ml) was added oxalyl chloride (0.3 ml, 2.52 mmol) and dimethylformamide (3 drops). After effervescing had subsided the reaction mixture was evaporated to dryness under reduced pressure. It was then dissolved in tetrahydrofuran (30 ml) and added to a solution of N,N-dimethylethylenediamine (0.405 g, 6.33mmol) and triethylamine (0.2 ml, 1.4 mmol) in tetrahydrofuran at 0° C. After 2 hours the reaction mixture was basified with 5M NaOH and water was added forming a white precipitate. This was filtered and dried to give the product a white solid (0.25 g, 45%), m.p. 91-93° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH:12]2[OH:25])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[C:27]1[N:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][CH:28]=1.[I-].[Na+]>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13][CH:12]2[O:25][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[N:32]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OC2CN(C(=O)OC(C)(C)C)CCOC2c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
Under ice-cooling, sodium hydride (60% in oil, 53 mg) was added to a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (400 mg) in DMF (5 mL). After stirring at room temperature for 20 min, methyl 6-chloropicolinate (280 mg) and sodium iodide (330 mg) were added, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (207 mg).