Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:35]/[O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)/[C:32]([O-])=[O:33])[N:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na+].[NH2:57][C@@H:58]1[C:77](=[O:78])[N:60]2[C:61]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[C:62]([C@H:65]3[CH2:69][CH2:68][CH2:67][O:66]3)[CH2:63][S:64][C@H:59]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[O:66]1[CH2:67][CH2:68][CH2:69][C@@H:65]1[C:62]1[CH2:63][S:64][C@@H:59]2[C@H:58]([NH:57][C:32](=[O:33])/[C:31](/[C:29]3[N:30]=[C:26]([NH:25][C:6]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[S:27][CH:28]=3)=[N:35]\[O:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:77](=[O:78])[N:60]2[C:61]=1[C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71]
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)C1=C([C@H]2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1=C([C@H]2CCCO2)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Yield: 67.8 %

Procedure:
Methanesulphonyl chloride (96μl, 1.25mmol) was added to sodium 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetate (852mg, 1.2mmol) in DMF (2ml) at <-40° C. The mixture was stirred 0.5h at -30±10° C. then t-butyl (6R,7R)-7-amino-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (326mg, 1mmol) in DMF (2ml), followed by pyridine (101μl, 1.25mmol), were added. The reaction was stirred for 1h without further cooling then diluted with ethyl acetate, washed twice with water and with brine, dried, concentrated in vacuo and flash chromatographed eluting with 25, 30% ethyl acetate in hexane to give the title compound as a colourless foam (665mg, 68%); vmax (CH2Cl2) 3395, 1787, 1722, 1687, 1527, 1449, 1156 and 1051cm-1 ; δH (CDCl3 /CD3OH) 1.55 (9H, s), 1.65-2.25 (4H, m), 3.32 and 3.40 (2H, ABq, J 17.6Hz), 3.8-4.0 (2H, m), 5.08 (1H, d, J 4.8Hz), 5.13 (1H, dd, J 7.0, 8.1Hz), 5.91 (1H, d, J 4.5Hz), 6.56 (1H, s), 7.2-7.5 (30H, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (1002)].
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][C:26](=O)[CH3:27])=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O.[OH-].[K+]>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]2[C:20]([CH2:23][CH2:24][N:25]=[C:26]2[CH3:27])=[CH:19][CH:18]=1
Reactant: COc1ccc(CCNC(C)=O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(C)=NCC2
Temperature: 25 °C
Yield: 32.5 %

Procedure:
Phosphorus pentoxide (22 g, 155.24 mmol) was added to a mixture of N-[2-(4-methoxyphenyl)-ethyl]-acetamide (50 g, 258.73 mmol) prepared in Step 1 and phosphorus oxychloride (48 ml, 517.46 mmol). The reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, added to ice water, basified with 2N potassium hydroxide solution, and then extracted with ethyl acetate. The organic layer washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 14.72 g of the titled compound as brown oil. (Yield: 32%) The product was used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]OS(C)(=O)=O)[CH:23]=2)[C:9]1=[O:34].[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.[K]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:39]3[C:35](=[O:45])[C:36]4=[CH:44][CH:43]=[CH:42][CH:41]=[C:37]4[C:38]3=[O:40])[CH:23]=2)[C:9]1=[O:34]
Reactant: CS(=O)(=O)OCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(S(C)(=O)=O)nc32)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccccc1Br)C2
Temperature: 90 °C
Yield: 99.2 %

Procedure:
A solution of 250 mg (0.44 mmol) of 3-(2-bromophenyl)-3,4-dihydro-7-(methanesulfonyl)-1-[3-(methanesulfonyloxymethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of dimethylformamide was treated with 111 mg (0.6 mmol) of potassium phthalimide and the mixture heated at 90° C. for 1 hour then cooled and evaporated. The residue was partitioned between 30 ml of dichloromethane and 30 ml of water. The organic phase was collected, dried over magnesium sulfate, filtered and evaporated to afford 270 mg (99%) of 3-(2-bromophenyl)-3,4-dihydro-7-(methanesulfonyl)-1-[3-(phthalimidomethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =618].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([CH2:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1.[CH3:17]OS(OC)(=O)=O>C1COCC1>[CH3:17][O:3][C:4]1([CH2:10][CH:11]=[C:12]([C:13]#[N:14])[C:15]#[N:16])[CH:5]=[CH:6][CH:7]=[CH:8][CH2:9]1
Reactant: COS(=O)(=O)OC
Reactant: N#CC(C#N)=CCC1(O)C=CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CC=C(C#N)C#N)C=CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a suspension of 60% NaH/mineral oil dispersion (2.9 g, 74.7 mmol) in THF (50 ml) was added dropwise (1-hydroxyphenylethylidene)malononitrile (13.8 g, 74.7 mmol) in THF (75 ml) over 25 minutes, followed by dimethylsulfate (7.1 ml, 74.7 mmol) in THF (50 ml) over 20 minutes. The reaction mixture was stirred at room temperature for 30 minutes, then at reflux for 4 hours. 0.5 equivalents of 60% sodium hydride and dimethylsulfate were added and the reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo, the residue was partitioned between ether and water, the organic layer was separated and the aqueous layer was extracted with ether (3×150 ml). The combined organic layers were dried over anhydrous MgSO4 and solvent was removed in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate/hexanes (1/1) to afford 8.4 g (56%) of (1-methoxyphenylethylidene)malononitrile as an amber liquid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[O:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].I[CH3:38]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH3:38])[C:19]2[O:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c(Cl)c1Cl)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)o1

Procedure:
2-(2,3-Dichloro-4-(3-methoxy-3-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propyl)phenoxy)-2-methyl propanoic acid using 2.1 equivalents of sodium hydride and 2.1 equivalents of iodomethane according to general procedure H.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CN1CCCC1)CO2

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), pyrrolidine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 315 (M+, 0.7), 110 (3), 85 (6), 84 (bp), 55 (4).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Br:12]N1C(C)(C)C(=O)N(Br)C1=O>C(OCC)(=O)C>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1ccc2ccccc2c1
Solvent: CCOC(C)=O
Product: BrCc1ccc2ccccc2c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Under nitrogen gas flow, 600 g of 2-methylnaphthalene was dissolved into 6,000 ml of ethyl acetate, the mixture was then added with 422 g of 1,3-dibromo-5,5-dimethylhydantoin, and heated to 40° C. The mixture was added with 7.4 g of V-65 from Wako Pure Chemical Industries, Ltd., and allowed to react at 40° C. for 7 hours. Thereafter, the reaction liquid was allowed to react at 65° C. for 3 hours, and then cooled. The reaction liquid was successively washed with aqueous sodium hydrogen carbonate solution and distilled water, and then concentrated. The concentrate was added with 3,600 ml of isopropanol, stirred for 30 minutes, added with 900 ml of distilled water, and further stirred for 30 minutes. Precipitated solid was collected by filtration, added with 1,800 ml of isopropanol, the mixture was stirred for 30 minutes, added with 450 ml of distilled water, and further stirred for 30 minutes. The resultant solid was collected by filtration, and dried, to thereby obtain 300 g of 2-bromomethylnaphthalene.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][CH2:41][C:42]([NH:44][C@H:45]([C:50]([OH:52])=[O:51])[CH2:46][C:47]([OH:49])=[O:48])=[O:43]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][CH2:41][C:42]([NH:44][C@H:45]([C:50]([OH:52])=[O:51])[CH2:46][C:47]([OH:49])=[O:48])=[O:43])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCC(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@@H](CC(=O)O)C(=O)O
Yield: 24.8 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (150 mg) prepared by the method described in Preparation A-2 (5) and N-(β-alanyl)-L-aspartic acid (150 mg), N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-aspartic acid (50 mg) was obtained as powder according to a similar manner to that of Example 2.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:13]3[C:14]([OH:15])=[C:10]([C:6]4[C:5]([CH3:25])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([F:9])[CH:7]=4)[CH:11]=[N:12]3)=[N:17][CH:18]=2)=[O:22])[CH2:30][C@@H:29]1[CH3:34])[CH3:27]
Reactant: CCN1CCNC[C@@H]1C
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4cc(F)c(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.30 (m, 6 H) 2.41 (s, 3 H) 2.79 (dt, J=12.95, 6.54 Hz, 2 H) 2.94-3.10 (m, 2 H) 3.13 (d, J=11.37 Hz, 1 H) 3.23 (dd, J=13.14, 8.34 Hz, 1 H) 3.46 (br. s., 1 H) 3.61-4.25 (m, 2 H) 7.59 (d, J=7.33 Hz, 1 H) 7.91-8.00 (m, 1 H) 8.03 (s, 1 H) 8.30 (d, J=13.14 Hz, 1 H) 8.45-8.57 (m, 2 H); ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]#[C:10][C:11]([C:13]1[N:14]([CH2:24][CH3:25])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>CCO>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[NH:29][N:28]=[C:11]([C:13]2[N:14]([CH2:24][CH3:25])[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCn1nc(-c2ccccc2)cc1C(=O)C#CCNC(=O)OC(C)(C)C
Solvent: O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)cc1-c1cc(CNC(=O)OC(C)(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To the above-prepared [4-(2-ethyl-5-phenyl-2H-pyrazol-3-yl)-4-oxo-but-2-ynyl]-carbamic acid tert-butyl ester in EtOH (5 mL), hydrazine monohydrate was added (excess, 5 drops), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to a thick oil, diluted with ethyl acetate, washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound (175 mg, 98% yeild) as a white foam. 1H NMR (CDCl3, 400 MHz): 7.86 (d, 2H); 7.39 (dd, 2H); 7.28 (dd, 1H); 6.72 (s, 1H); 6.36 (s, 1H); 5.12 (broad dd, 1H); 4.58 (q, 2H); 4.31 (d, 2H); 1.49 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)[O:3]1>CO.[Pd]>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:22])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)[O:5]1
Reactant: CCOC(=O)C=Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 97.1 %

Procedure:
A solution of 8 g (26.4 mmol) of ethyl 3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]acrylate in 30 mL of methanol is stirred for one hour at room temperature in the presence of 400 mg of 10% palladium-on-charcoal under a hydrogen atmosphere. The catalyst is filtered off and the solvents are then evaporated off. 7.8 g of ethyl 3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate are obtained. Yield=96%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(O)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
3-Bromo-4-methylphenol(25.0 g, 0.134 mol) and aluminum chloride (36.11 g, 0.27 mol) were heated to 127° C. for 2 h. Ice was added, the solution extracted with ethyl acetate, dried (Na2SO4) and evaporated to dryness under reduced pressure. N,N-Dimethyl formamide (150 ml), t-butyl-dimethylchlorosilane (25.0 g, 165 mmol) and imidazole (22.6 g, 33.2 mmol) were added and the solution stirred at room temperature for 16 h. The products were partitioned between water and ethyl acetate, the organic layer separated, dried (Na2SO4) and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane as eluent gave impure 1-bromo-2-methyl-5-t-butyldimethylsilyloxybenzene (22.0 g). Carbon tetrachloride (125 ml) and N-bromosuccinimide (10.80 g, 66.6 mmol) were added and the solution heated to reflux over a 150 W light bulb for 2 h. The solution was cooled to 5° C., filtered and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane as eluent gave the title compound (12.64 g, 21%) as a white solid; δH (CDCl3) 0.21 (6H, s, Si(CH3)2), 0.97 (9H, s, t-Bu), 4.59 (2H, s, CH2Br), 6.76 (1H, dd, J 8.3 and 2.4 Hz, 4-H), 7.07 (1H, d, J 2.4 Hz, 6-H), 7.30 (1H, d, J 8.4 Hz, 3-H): m/z (E.I.) 382 (M+, 2%), 380 (M+, 4%), 378 (M+, 2%), 299 (100%): (Found: M-, 377.9647). C13H20OBr2Si requires M, 377.9650).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].P(Cl)(Cl)Cl.[NH2:11][C:12]1[S:13][C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:15]([C:17](O)=[O:18])[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[NH2:11][C:12]1[S:13][C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:15]([C:17](=[O:18])[NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[N:16]=1
Reactant: Nc1nc(C(=O)O)c(-c2ccncc2)s1
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: CN(C)CCNC(=O)c1nc(N)sc1-c1ccncc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of N,N-dimethylethylenediamine (0.59 ml) in pyridine (10 ml) were added phosphorus trichloride (1.3 g) and 2-amino-5-(4-pyridyl)-4-thiazolecarboxylic acid (1.5 g) and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was poured into water (50 ml), adjusted to pH 8 with aqueous potassium carbonate and extracted with a mixture of chloroform and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo to give 2-amino-4-[N-[2-(N,N-dimethylamino)ethyl]carbamoyl]-5-(4-pyridyl)thiazole (0.4 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.I[C:7]1[CH:8]=[C:9]([CH:19]=[CH:20][CH:21]=1)[CH2:10][C:11]1([CH3:18])[NH:16][C:15](=[O:17])[CH2:14][O:13][CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:18][C:11]1([CH2:10][C:9]2[CH:19]=[CH:20][CH:21]=[C:7]([N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[CH:8]=2)[NH:16][C:15](=[O:17])[CH2:14][O:13][CH2:12]1
Reactant: CC1(Cc2cccc(I)c2)COCC(=O)N1
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(Cc2cccc(-n3nccn3)c2)COCC(=O)N1
Temperature: 25 °C

Procedure:
DMCDA (85 μL, 0.538 mmol) followed by 1H-1,2,3-triazole (0.31 mL, 5.38 mmol) were added to a mixture of rac-5-(3-iodo-benzyl)-5-methyl-morpholin-3-one H-8 (890 mg, 2.69 mmol), Cs2CO3 (1.75 g, 5.38 mmol) and CuI (77 mg, 0.40 mmol) in DMF (5 mL) under argon and the resulting blue suspension was heated to 120° C. for 18 h. The reaction mixture was cooled to RT before being quenched with water and filtered over celite rinsing with water and DCM. The layers were separated and the aqueous phase was re-extracted with DCM (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (eluting with a gradient of 75% to 100% EtOAc in hexane) to give the title compound as a pale brown solid. LC-MS A: tR=0.69 min; [M+H]+=273.21.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C@@H:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:6].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30](/[CH:33]=[CH:34]/[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43](O)=[O:44])[CH2:38]2)=[O:36])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C@@H:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:6][C:43]([C@@H:39]1[CH2:40][CH2:41][CH2:42][N:37]([C:35](=[O:36])/[CH:34]=[CH:33]/[CH:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:26])[CH2:28][CH2:29]2)[CH2:38]1)=[O:44]
Reactant: COC(=O)C[C@H](N)CCc1ccc(OC)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@@H](CCc1ccc(OC)c(OC)c1)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a mixture of 3(R)-(3,4-dimethoxyphenethyl)-β-alanine methyl ester (0.87 g), (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (1.19 g) and 1-hydroxybenztriazole (0.44 g) in dimethylformamide (9 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.59 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: n-hexane=(5:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine methyl ester as a colorless oil (1.83 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36](Br)=[CH:37][CH:38]=1)(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (210 mg, 71%). MS (ISN) 586.1 [(M−H)−]; mp 197° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=3)=[CH:4][CH:3]=2)[CH:28]=1
Reactant: Nc1cccnc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3cccnc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 71 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), Pyridin-3-ylamine (0.24 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give Pyridin-3-yl-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine as brown solid in 71% yield.