Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:33])[N:24]([CH2:29][CH2:30][C:31]#[N:32])[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]=[C:19]([Cl:34])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:31]([CH2:30][CH2:29][N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:23](=[O:33])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=[C:19]([Cl:34])[CH:20]=1)(=[O:39])[NH2:32]
Reactant: CC(C)CN(CCC#N)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(CCC(N)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 18 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-isobutyl-carbamoyl]-phenoxy}ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.059 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.047 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]C)=O.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[C:17]([NH:21][C:13]([C:3]1[C:4](=[O:12])[NH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1c(O)c2ccccc2[nH]c1=O
Solvent: CCO
Product: CC(C)(C)NC(=O)c1c(O)c2ccccc2[nH]c1=O

Procedure:
8.76 g (0.04 mol) of methyl 4-hydroxy-2-oxoquinoline-3-carboxylate was stirred with 3.7 g (0.05 mol) of tert-butylamine in 60 ml of ethanol in a miniautoclave for 8 hours at 150° C. under autogenous pressure. After cooling, the crystals were removed by suction filtration, washed with ligroin and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:20]=3)(=[O:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(F)cc2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccc(F)cc2)c1
Yield: 65.8 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from [3-(4-fluorophenyl)phenyl]sulfonyl chloride (15 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 13 mg (66%) of the title compound. MS (ESI+) calcd for C19H14FN5O2S 395.085224, found 395.085454.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[CH:28]([CH2:32][CH2:33][CH3:34])[C:29](O)=[O:30]>>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][NH:26][C:27](=[O:35])[CH:28]([CH2:32][CH2:33][CH3:34])[C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CCCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CCCC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=519.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-propyl-malonamic acid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH:63]=[CH2:64])[CH2:45]2)[CH:7]([CH3:66])[CH:6]([OH:67])[CH2:5][C:4]1=[O:68])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[N:56]([CH3:60])[CH:55]=[CH:54]4)[CH:46]([O:61][CH2:62][CH2:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH:6]([OH:67])[CH2:5][C:4]1=[O:68])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2c(ccn2C)c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (14 mg) in ethyl acetate (400 μl) was added rhodium on carbon (4 mg). The flask was filled with hydrogen, and the mixture was stirred at room temperature. After 1.5 hours the mixture was filtered through Celite then the solvent was removed in vacuo. Purification by flash chromatography (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (10 mg). partial 1H NMR d: 7.17 (s, 1H); 7.15 (d, J=9 Hz, 1H); 6.97 (d, J=3 Hz, 1H); 6.92 (dd, J=9, 3 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.56 (brd, J=4 Hz, 1H); 4.40 (brd, J= 14 Hz, 1H); 3.71 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=C)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC([OH:26])C>O.O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=[O:26])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 6 h

Procedure:
4-But-3-enyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (13.5 g, 43.48 mmol, 1 eq) was dissolved in i-PrOH (217 mL) and a solution of NaIO4 (20.23 g, 94.6 mmol, 2.18 eq) in 217 mL of water was added followed by OsO4 (37 mg, 0.144 mmol, 0.003 eq). The reaction mixture was vigorously stirred for 6 h. The reaction mixture was then quenched with 1500 mL of water, transferred to a separatory funnel and extracted with ethyl acetate (3×200 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (300 g column, 30% EtOAc in heptanes; 50 mL/min). This gave 8.5 g (63%) of the title compound as a beige oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#C[Si](C)(C)C)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 3 hours with 1.30 g (12.5 mmol) of ethynyltrimethylsilane, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate/hexane (1:1). After crystallization from ethyl acetate and hexane there was obtained 7-chloro-4,5-dihydro-5-methyl-3-[(trimethylsilyl)ethynyl]-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 186°-187°.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:9]2)=[CH:4][CH:3]=1.[N:21]([CH2:24][CH3:25])=[C:22]=[O:23]>CN(C)C=O>[CH2:24]([NH:21][C:22]([N:16]1[CH2:17][CH2:18][CH:13]([C:8]2[O:9][C:10]3[C:5]([C:6](=[O:20])[C:7]=2[CH3:19])=[CH:4][CH:3]=[C:2]([OH:1])[C:11]=3[CH3:12])[CH2:14][CH2:15]1)=[O:23])[CH3:25]
Reactant: CCN=C=O
Reactant: Cc1c(C2CCNCC2)oc2c(C)c(O)ccc2c1=O
Solvent: CN(C)C=O
Product: CCNC(=O)N1CCC(c2oc3c(C)c(O)ccc3c(=O)c2C)CC1
Reaction time: 48 h
Yield: 60.4 %

Procedure:
To a solution of 7-hydroxy-3,8-dimethyl-2-(piperidin-4-yl)-4H-chromen-4-one (68 mg, 0.25 mmol) obtained in Example 7-2 in dimethylformamide (2 mL), isocyanatoethane (19 μL, 0.25 mmol) was added dropwise under cooling with ice, and then the mixture was brought back to room temperature and stirred for 2 days. The reaction solution was concentrated, and then the obtained residue was purified by reverse-phase HPLC to obtain 52 mg of the title compound (yield: 59%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15]O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Na+].[I-:18]>>[I:18][CH2:15][CH2:14][CH2:13][C:12]#[C:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C#CCCCO)cc1
Reactant: [I-]
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(C#CCCCI)cc1

Procedure:
Preparation of the title compound with tosylated alcohol of Example 19, 5-(4-methanesulfonylphenyl)pent-4-yn-1-ol (3.14 g, 8.35 mmol), NaI (6.26 g, 41.76 mmol) following the procedure of Example 54 yielded 2.8 g (96%) of the title compound as a red oil: NMR (CDCl3) δ 2.06-2.15 (m, 2H), 2.58-2.63 (t, J=6.78, 2H), 3.04 (s, 3H), 3.33-3.37 (t, J=6.69, 2H), 7.57 (d, J=1.77, 2H), 7.85 (d, J=4.95, 2H). MS m/z 348.9 (M+H cald. for C12H13IO2S 348=349.2).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:44]([N+:48]1[N:52]=[C:51]([CH3:53])[S:50][C:49]=1[CH3:54])[CH2:45][CH2:46][CH3:47]>>[CH2:44]([N:48]1[N:52]=[C:51]([CH3:53])[S:50]/[C:49]/1=[CH:54]\[C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[CH2:45][CH2:46][CH3:47]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: Cc1ccsc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-methylthiophene-2-carboxylic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3H) 1.28-1.39 (m, 2 H) 1.69-1.79 (m, 2 H) 2.45-2.48 (m, 3 H) 4.15 (t, 2 H) 6.18-6.22 (m, 1 H) 6.97 (d, 1 H) 7.55 (d, 1 H); MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18].CN1CCOCC1>C(Cl)Cl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:16]([N:11]2[C:12]3[C:8](=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.59 mL, 20.4 mmol) was added to a stirred solution of 3b (6.67 g, 19.5 mmol) and 4-methylmorpholine (2.78 mL, 25.3 mmol) in DCM (100 mL) at 0° C. After 30 min, an additional portion of methanesulfonyl chloride (0.80 mL, 10.2 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-50% EtOAc/hexanes as eluent) to afford the title compound 25. m/z (ES) 421 (MH)+; IP=A rating
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[CH2:40](O)[CH2:41][CH2:42][OH:43].CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[O:43]1[C:2]2([CH2:7][CH2:6][CH:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]5[NH:32][C:31](=[O:33])[O:30][N:29]=5)=[CH:20][CH:21]=4)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]4[N:37]=[CH:38][N:39]=[C:9]34)[CH2:4][CH2:3]2)[O:1][CH2:40][CH2:41][CH2:42]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCCO3)c2ncnn12
Yield: 39.2 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.20 g), propane-1,3-diol (0.058 g), 4-methylbenzenesulfonic acid (0.0072 g) and toluene (20 mL) was heated under reflux for 3 hr using a Dean-Stark trap. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.087 g, 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([N:37]=[C:38]=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)[C:38]([NH:37][C:29]2[CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=[C:27]([C:26]([F:25])([F:40])[F:41])[CH:28]=2)=[O:39])=[CH:8][CH:9]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
4-((4-Cyclohexylphenylamino)methyl)benzoic acid methyl ester (2.38 g, 7.36 mmol) was dissolved in DCM (150 mL) and 3,5-bis(trifluoromethyl)phenyl isocyanate (1.36 mL, 8.10 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water (3×15 mL), dried (magnesium sulphate) and concentrated in vacuo to afford 4.3 g of 4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.[OH-:17].[Na+].OO>C(O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH2:8])=[O:17])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: [OH-]
Reactant: COc1ccc(-c2snc(Cl)c2C#N)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2snc(Cl)c2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-chloro-5-(4-methoxyphenyl)-1,2-thiazole-4-carbonitrile (3.4 g, 13.56 mmol, 1.00 equiv) in ethanol/H2O (20/10 mL), sodium hydroxide (1 g, 25.00 mmol, 1.84 equiv), H2O2 (10 g). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×80 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 680 mg (crude) of 3-chloro-5-(4-methoxyphenyl)-1,2-thiazole-4-carboxamide as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C11H9ClN2O2S, 269.0 (M+H). found 269.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([C:17]3[N:18]=[C:19]4[C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:20]4=[N:21][CH:22]=3)[CH:10]=[C:11]([O:13][CH2:14]OC)[CH:12]=2)[CH2:3]1.[CH3:41][N:42]([CH3:46])[CH2:43]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:41][N:42]([CH3:46])[CH2:43][CH2:14][O:13][C:11]1[CH:10]=[C:9]([C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:24][N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[C:20]3=[N:21][CH:22]=2)[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][C:2]([CH3:40])([CH3:1])[CH2:3]2)[CH:12]=1
Reactant: CN(C)CCO
Reactant: COCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCC(C)(C)C2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCC(C)(C)C2)c1

Procedure:
A flask was charged with 1-[2-[3-(3,3-dimethyl-pyrrolidin-1-yl)-5-methoxymethoxy-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (90 mg, 0.17 mmol), 2-dimethylamino-ethanol (reagent A, 0.04 ml, 0.34 mmol) and triphenylphosphine (reagent B, 90 mg, 0.34 mmol). THF (2 ml) was added under nitrogen atmosphere. Diisopropyl azodicarboxylate (reagent C, 0.07 ml, 0.34 mmol) was added via syringe and the material was stirred. After 1 hour a further 2 equivalents each of reagents A, B and C were added. The mixture was stirred overnight. The crude was loaded onto 2 preparative TLC plates eluting with 3% MeOH in dichloromethane. The plates were dried and re-developed with the solvent system. This process was repeated once more and then product band was collected providing 1-[2-[3-(2-dimethylamino-ethoxy)-5-(3,3-dimethyl-pyrrolidin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one, 56 mg, as a golden yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>C(O)C>[CH2:12]([NH:14][C:15]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[S:16])[CH3:13]
Reactant: CCN=C=S
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: CCNC(=S)NCCSCc1[nH]cnc1C
Yield: 86.4 %

Procedure:
i. A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (6.9 g.) and ethyl isothiocyanate (3.84 g.) in ethanol was heated under reflux for 2 hours. Concentration followed by recrystallisation of the residue from aqueous ethanol gave N-ethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (9.0 g.), m.p. 140°-141°. (Found: C, 46.5; H, 7.1; N, 21.7; S, 25.1. C10H18N4S2 requires: C, 46.5; H, 7.0; N, 21.7; S, 24.8).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@:12]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of (1S,4S)-4-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopent-2-ene-1-carboxylic acid (9.78 g, 36.3 mmol) in ethanol (250 mL) was added 10% palladium on carbon (550 mg). The mixture was shaken under hydrogen at 55 psi overnight and filtered through celite. The filtrate was evaporated in vacuo to afford the title compound (9.45 g, 96%). MS calculated for C14H25NO4: (M+H)+ 272; found 172.1 (M-Boc+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[CH2:19][CH2:18][NH:17]1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[S:24][CH:23]=[CH:22][C:21]=4[CH:16]3[CH2:14][CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCC1NCCc2sccc21
Product: CCC1c2ccsc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 79 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-ethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([NH:21][NH2:22])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:19]([C:18]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:17]=3[F:16])=[N:21][N:22]=2)[N:3]=1
Reactant: CC1(c2cc(Cl)nnc2Cl)CCCCC1
Reactant: NNC(=O)c1ccc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: CC1(c2cc3nnc(-c4ccc(F)cc4F)n3nc2Cl)CCCCC1
Yield: 38.7 %

Procedure:
A mixture of 3,6-dichloro-4-(1-methylcyclohexyl)pyridazine (1.29 g, 5.27 mmol), 2,4-difluorobenzoic hydrazide (1.72 g, 10 mmol) and triethylamine hydrochloride (1.09 g, 7.9 mmol) in p-xylene (5 ml) was stirred and heated at reflux for 24 hours. Upon cooling, the volatiles were removed in vacuo and the residue was partitioned between dichloromethane (100 ml) and water (100 ml) and NaHCO3 (100 ml). Undissolved solid was removed by filtration. The layers were separated and the aqueous was further extracted with dichloromethane (2×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with 0%→25% ethyl acetate in dichloromethane to give the required product (0.74 g): 1H NMR (250 MHz, CDCl3) δ 1.34-1.74 (6H, m), 1.50 (3H, s), 1.90-2.15 (4H, m), 7.01-7.14 (2H, m), 7.87-7.98 (1H, m), 8.18 (1H, s); MS (ES+) m/e 365 [MH], 363 [MH]+.