Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[C:13]1([NH2:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O>[N+:10]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Product: N#Cc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A suspension of 3-fluoro-4-nitrobenzonitrile (1.66 g, 10.0 mmol) in DMSO (5 mL) was purged with a stream of argon prior to addition of phenylamine (1.82 mL, 20.0 mmol) and then the mixture was stirred at 120° C. for 1 h under an argon atmosphere. After cooling to RT, the reaction mixture was partitioned between EtOAc (75 mL) and an aqueous solution of KHSO4 (100 mL). The organic layer was then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with diethyl ether affording 4-Nitro-3-phenylaminobenzonitrile as red crystals (2.35 g, 98%). 1H NMR (CDCl3, 400 MHz): δ 9.48 (1H, bs), 8.29 (1H, d, J=8.76 Hz), 7.53-7.40 (3H, m), 7.35 (1H, t, J=7.52 Hz), 7.29-7.22 (2H, m), 6.97 (1H, d, J=8.79 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=[C:9]([NH:18]C(=O)C(C)(C)C)[S:8]1.[BH4-].[Na+]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=[C:9]([NH2:18])[S:8]1
Reactant: COC(=O)CCCC1(c2ccccc2)SC(NC(=O)C(C)(C)C)=NN1C(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)CCCC1(c2ccccc2)SC(N)=NN1C(=O)C(C)(C)C
Yield: 16.4 %

Procedure:
In the same manner as that of the method described in to WO2003/051854, from 4-[3-(2,2-dimethylpropionyl)-5-(2,2-dimethylpropionylamino)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]butanoic acid methyl ester (11.2 g, 25.9 mmol) obtained according to the method described in WO2003/051854 and sodium borohydride (2.94 g, 77.6 mmol), 4-[5-amino-3-(2,2-dimethylpropionyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]butanoic acid methyl ester (1.54 g, 17%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[C:56]([O:60][C:61](=[O:79])[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][NH2:78])([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C.C1COCC1>[C:56]([O:60][C:61](=[O:79])[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][NH:78][C:16](=[O:18])[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)CCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
3-[(2-Benzyloxycarbonylethyl) tert-butoxycarbonylamino]propionic acid (0.17 g, 0.48 mmol) was dissolved in DMF (2 mL) and HOBt (0.065 g, 0.48 mmol) and EDAC (0.093 g, 0.48 mmol) were added. The mixture was stirred for 30 min., and DIEA (0.083 mL, 0.48 mmol) was added and 17-aminoheptadecanoic acid tert-butyl ester (0.15 g, 0.44 mmol) dissolved in THF (3 mL)+DMF (0.5 mL) was added. The reaction was stirred for 2 days. The reaction was concentrated and the residue was dissolved in AcOEt (50 mL) and washed with 0.2 N HCl (2×15 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. The product was purified by flash chromatography (Silica) eluting with AcOEt/Heptane (1:1, 7:3, 8:2) then DCM, DCM:methanol (8:2) and 5% AcOH in DCM. The appropriate fractiones were pooled and concentrated under vacuum. The residue was dissolved in DCM. Silica was added and the product was concentrated onto the silica under vacuum. The silica was used in another flash chromatography, eluting with AcOEt/heptane (3:7 and 1:1). The appropriate fractiones were pooled and concentrated under vacuum to yield 135 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:13](=[O:14])[CH2:12][CH:11]2[CH:7]1[CH2:8][C:9]1([O:18][CH2:17][CH2:16][O:15]1)[CH2:10]2)=[O:5])[CH3:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:1]([O:3][C:4]([CH:6]1[C:13](=[O:14])[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9]1([O:15][CH2:16][CH2:17][O:18]1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)CC2CC3(CC21)OCCO3
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCOC(=O)C1C(=O)C[C@@H]2CC3(C[C@H]12)OCCO3
Reaction time: 68 h
Yield: 43.8 %

Procedure:
Using Saccharomyces carlsbergensis IFO 0565 cultivated similarly to Example 3 and 500 mg of (1SR,5RS)-2-ethoxycarbonyl-7,7-ethylenedioxybicyclo[3.3.0]octan-3-one (VIII), reaction was initiated in a similar manner as described in Referential Example 3. 10 g of glucose after 4 hours and 10 g after 23 hours were added and shaken for 68 hours. Aftertreatment of a reaction mixture in a similar manner as described in Referential Example 3 gave 219 mg of (1S,5R)-2-ethoxycarbonyl-7,7-ethylenedioxybicyclo[3.3.0]- octan-3-one (IV).
Reaction SMILES: I.CS[C:4]([C:6]1[S:7][C:8]2[C:14]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=2[N:10]=1)=[NH:5].[CH2:23]([N:30]1[CH2:35][CH2:34][C:33](OCC)(OCC)[CH:32]([NH2:42])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.CCOCC>O1CCCC1>[CH2:23]([N:30]1[CH2:35][CH2:34][C:33]2[N:5]=[C:4]([C:6]3[S:7][C:8]4[C:14]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[CH:13][CH:12]=[C:11]([O:21][CH3:22])[C:9]=4[N:10]=3)[NH:42][C:32]=2[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=N)SC)nc12
Reactant: CCOC1(OCC)CCN(Cc2ccccc2)CC1N
Agent: FB(F)F
Agent: I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CN(Cc3ccccc3)CC4)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
To a suspension of 0.04 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboximidothioic acid methyl ester hydroiodide in 1.8 ml tetrahydrofurane were added 0.1 g 1-benzyl-4,4-diethoxy-piperidin-3-ylamine in 1.8 ml tetrahydrofurane and the mixture was stirred at room temperature for 16 hours. Then 0.015 ml boron trifluoride etherate was added and the solvent was distilled off under vacuum. Again 0.015 ml boron trifluoride etherate was added and the mixture was dissolved in 1.5 ml dimethylformamide and heated for 15 minutes at 125° C. The solvent was distilled off and the residue was dissolved in dichloromethane and extracted with water. The organic layer was dried with sodium sulfate, filtered and the solvent was evaporated. Chromatography on silicagel with ethylacatate/heptane 1:1 to 2:1 yielded 0.4 mg (1%) 5-benzyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine as an amorphous solid; m/e=462 (M+H+).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][NH:16][C:17]1[N:22]2[N:23]=[C:24]([CH3:40])[C:25]([C:26]3[C:31]([Cl:32])=[CH:30][C:29]([C:33]#[C:34][Si](C)(C)C)=[CH:28][C:27]=3[Cl:39])=[C:21]2[N:20]=[C:19]([CH3:41])[CH:18]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)(C)(C)C.[OH-].[K+]>C(O)C>[Cl:39][C:27]1[CH:28]=[C:29]([C:33]#[CH:34])[CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]1[C:24]([CH3:40])=[N:23][N:22]2[C:17]([NH:16][CH2:15][CH2:14][NH:7][CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:18][C:19]([CH3:41])=[N:20][C:21]=12
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCOCC2)n2nc(C)c(-c3c(Cl)cc(C#C[Si](C)(C)C)cc3Cl)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#Cc1cc(Cl)c(-c2c(C)nn3c(NCCNC4CCOCC4)cc(C)nc23)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a stirred solution of {2-[3-(2,6-dichloro-4-trimethylsilanylethynyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (1.2 g, 2.0 mmol) in ethanol (2 mL) was added KOH (0.2 g, 8 mmol). After 1 hour, the reaction was cooled to 0° C. and 1:1 ethanol/concentrated aqueous hydrochloric acid (4 mL) was added and the mixture was allowed to warm to room temperature. After 1 day, the reaction was concentrated under reduced pressure, extracted from saturated aqueous sodium bicarbonate with methylene chloride, the combined extracts were dried (Na2SO4), concentrated under reduced pressure, and then chromatographed (4:1 to 10:3 to 3:2 ethyl acetate/methanol) to afford the title compound (0.70 g, 78%) as an off-white solid: +APcI MS (M+1)+458; 1H NMR (methanol-d4) δ: 7.58 (d, 1H), 6.10 (s, 1H), 3.76 (s, 1H), 2.39 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH:28]2[CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:28]1([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:31][C:32]3[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: NC(=O)c1ccc(Nc2nc(NC3CC3)c3c(-c4ccncc4)c[nH]c3n2)cc1
Temperature: 135 °C
Reaction time: 48 h
Yield: 7.6 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (135 mg, 0.307 mmol), 4-aminobenzamide (100 mg, 0.735 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (3 mL) was stirred at 135° C. for 48 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 386.2 (M+H); UV 201.8, 309.8 nm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)nc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)nc3)cc2c1
Yield: 86 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (230 mg, 0.41 mmol) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 3.2 mL) was stirred at 25° C. for 16 h. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous ammonium chloride solution (4×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (150 mg, 86%) which was used in the next step without further purification: LC/MS m/e calcd for C22H23N3O4S [M+H]+ 426.51, observed 426.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24](O)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:36]4[CH2:37][CH2:38][CH:33]([N:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH2:34][CH2:35]4)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCC(N3CCOCC3)CC2)n[nH]1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 4-morpholinopiperidine. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-96:4). 1H NMR (400 MHz, DMSO-d6): about 1.32 (2H, m), about 1.82 (2H, m), 2.45-2.47 (5H, m), about 2.78 (1H, m), 2.95 (2H, t), about 3.11 (1H, m), 3.55-3.57 (6H, m), about 4.45 (1H, m), 6.34 (1H, d), 7.02 (1H, d), about 7.03 (1H, broad s), 7.59 (1H, distorted dd), 7.63 (1H, distorted d), 7.84 (1H, d), 8.6 (1H, broad s), 13.9 (1H, broad s).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)OC(C)(C)C)cc34)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCN)cc34)cc2C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a suspension of (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester (1.22 g, 2.46 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL) dropwise. The reaction was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with CH2Cl2 (30 mL) and aqueous saturated sodium bicarbonate. Phases were separated and the aqueous layer was extracted with CH2Cl2 (30 mL). Organic layers were combined, dried over sodium sulfate and concentrated to give the crude product (0.85 g, 88%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:17][CH2:18]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:11][O:12][CH2:18][CH2:17][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: OC[C@@H](O)COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Product: c1ccc(COC[C@H]2COCCO2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(2R)-3-(benzyloxy)propane-1,2-diol (2.00 g, 11.0 mmol) and tetrabutylammonium bromide (708 mg, 2.20 mmol) were dissolved in 50 mL of 1,2-dichloroethane, then 50 mL of a 50% (w/w) aqueous sodium hydroxide solution was added quickly and the mixture was heated to 50° C. After 18 h, an additional 50 mL of 1,2-dichloroethane and 50 mL of 50% (w/w) sodium hydroxide solution was added. After 8 h, additional 50 mL of 1,2-dichloroethane was added. After 72 h, the mixture was diluted in diethyl ether, washed with water and brine, then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, ethylacetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 7.26-7.35 (m, 5H); 4.51-4.56 (m, 2H); 3.72-3.82 (m, 4H); 3.67-3.71 (m, 1H); 3.58-3.64 (m, 1H); 3.38-3.48 (m, 3H).
Reaction SMILES: CO.[CH2:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:4].[S:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11].C([O:24][C:25](=O)[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])OCC)C>C(O)(=O)C>[CH2:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:4].[CH3:35][S:32]([NH:31][C:27]1[NH:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([S:10]([OH:13])(=[O:11])=[O:12])=[CH:19][CH:18]=2)[C:25](=[O:24])[CH:26]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)C=C(NS(C)(=O)=O)OCC
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1cc(=O)n(-c2ccc(S(=O)(=O)O)cc2)[nH]1

Procedure:
Into a mixed solution of 50 ml of methanol, 50 ml of triethylamine and 50 ml of glacial acetic acid there was dissolved 18.8 g of p-sulfophenyl hydrazine, to which was added 23.5 g of ethylβ-methanesulfonylamino-β-ethoxyacrylate. The resulting solution was allowed to stand at room temperature for one week. The crystals precipitated were collected and recrystallized from methanol; thus 29 g of plate-like crystals of the objective compound of a melting point of 236° to 238° C. was obtained.
Reaction SMILES: CO[C:3]1[CH:19]=[C:18]([NH:20][C:21]2[C:22]3[N:23]([CH:32]=[CH:33][N:34]=3)[C:24]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:25][N:26]=2)[CH:17]=[CH:16][C:4]=1C(NCC1C=NC(C)=CC=1)=O.BrC1N2C=CN=C2C(NC2C=CC([CH:52]3[CH2:57][CH2:56][N:55]([CH:58]([CH3:60])[CH3:59])[CH2:54][CH2:53]3)=CC=2)=NC=1>>[CH:58]([N:55]1[CH2:56][CH2:57][CH:52]([C:4]2[CH:3]=[CH:19][C:18]([NH:20][C:21]3[C:22]4[N:23]([CH:32]=[CH:33][N:34]=4)[C:24]([C:27]4[CH:28]=[N:29][NH:30][CH:31]=4)=[CH:25][N:26]=3)=[CH:17][CH:16]=2)[CH2:53][CH2:54]1)([CH3:60])[CH3:59]
Reactant: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)ccc1C(=O)NCc1ccc(C)nc1
Reactant: CC(C)N1CCC(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Product: CC(C)N1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1

Procedure:
This step may be performed using the same methods as described for Compound 184, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(1-isopropylpiperidin-4-yl)-phenyl]amine. LCMS: Rt 0.78 min (100%) m/z (ESI) 402 (M+H)+.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[C:26](Cl)(Cl)=[S:27]>C(Cl)(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:16]=[C:26]=[S:27])=[CH:17][CH:18]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=C(Cl)Cl
Reactant: CCCCCc1ccc(-c2ccc(N)cc2)nc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(-c2ccc(N=C=S)cc2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1.256 g of p-(5-pentyl-2-pyridyl)aniline in 29 ml of chloroform was treated at 5° C. under nitrogen with 1.46 ml of triethylamine. Then, at 1° C. within 20 minutes a solution of 0.49 ml of 95 percent thiophosgene in 14.5 ml of chloroform was added dropwise to the reaction mixture so that the temperature did not exceed 3° C. The reaction mixture was subsequently stirred at room temperature for 45 minutes and under reflux for a further 40 minutes, then cooled and washed with 40 ml of 3N ammonia and with water. The aqueous phases were back-extracted with methylene chloride. The organic phases were dried over sodium sulphate, filtered and freed from solvent. Purification of the resulting brownish paste (1.56 g) by chromatography on 60 g of silica gel with 700ml of methylene chloride/hexane (vol. 1:1) and subsequent crystallization from diethyl ether/hexane gave 1.17 g of p-(5-pentyl-2-pyridyl)phenylisothiocyanate as colourless crystals with m.p. (C--SA) 36.3° C. and cl.p. (SA --I) 97.2° C.
Reaction SMILES: [OH:1]S(O)(=O)=O.[C:6]([NH:9][C:10]12[CH2:19][C:14]3([CH3:20])[CH2:15][CH:16]([CH2:18][C:12]([CH3:21])([CH2:13]3)[CH2:11]1)[CH2:17]2)(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]12[CH2:19][C:14]3([CH3:20])[CH2:15][C:16]([OH:1])([CH2:18][C:12]([CH3:21])([CH2:13]3)[CH2:11]1)[CH2:17]2)(=[O:8])[CH3:7]
Reactant: CC(=O)NC12CC3CC(C)(CC(C)(C3)C1)C2
Reactant: O=S(=O)(O)O
Product: CC(=O)NC12CC3(C)CC(C)(CC(O)(C3)C1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Fuming H2SO4 (3 mL) was added to 1-acetamido-3,5-dimethyladamantane (0.2 g) at 0° C. under nitrogen and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured onto ice (10 g) and the product was extracted with ether (10 mL×4). The combined ether solution was washed with brine (10 mL) and water (10 mL). The solution was dried using sodium sulfate. The solvent was removed in vacuo and, after crystallization on standing, 70 mg of white product was obtained. Pure product was obtained by recrystallization in ether. 1H NMR (DMSO-d6, ppm): 7.30 (brs, 1 H, NH), 4.37 (brs, 1H, OH), 1.72 (s, 3H, COCH3), 1.65 (s, 2H), 1.47 (s, 4H), 1.24-1.14 (dd, 4H, J=11.2, 23.9 Hz), 0.99 (s, 2H), 0.82 (s, 6H, 2×CH3). m.p. 194-195° C. Anal. (C14H23NO2), C. H. N.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:6].CS[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1>N1C=CC=CC=1>[CH3:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:17][N:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: CN(CCCN)c1ccccn1
Solvent: c1ccncc1
Product: CN(CCCNc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-methylamino]pyridine (1.0 g) and 2-methylthio-5-(4-chlorobenzyl)pyrimid-4-one (1.33 g) were heated together under reflux in pyridine (3 ml) for 20 hr. The mixture was stripped and the residue recrystallised twice from ethanol to give 2-[3-(N-methyl-N-pyrid-2-ylamino) propylamino]-5-(4-chlorobenzyl)pyrimid-4-one 0.5H2O. 1.16 g (59%) mp ca. 65° C. (softens).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[CH:23](O)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH:23]=[O:24])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O
Reactant: O=CO
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(NC=O)cc2C(Oc2ccnc(O)c2)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated. After customary working up, 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-formamido-3-chromanol is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:30]([C:32]1([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)#[CH:31]>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:31]#[C:30][C:32]4([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC1(O)CCCCC1
Reactant: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCNc1nc2ccc(C#CC3(O)CCCCC3)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 18.9 %

Procedure:
A mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine (150 mg, 0.39 mmol, 95%), triethylamine (2 mL), 1-ethynylcyclohexan-1-ol (300 mg, 2.42 mmol) and bis(triphenylphosphine)palladium(II) dichloride (300 mg, 0.43 mmol) in dimethylsulfoxide (3 mL) was stirred under nitrogen for 1 hr at 70° C. The reaction mixture was purified on a C18 column (acetonitrile/water, 5:95-80:20) to give 30 mg (19%) of 1-[2-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]ethynyl]cyclohexan-1-ol as a white solid: 1H NMR (300 MHz, DMSO) delta 8.43 (d, J=5.4 Hz, 1H), 8.22 (d, J=5.4 Hz, 1H), 7.50 (s, 1H), 7.30-7.10 (m, 4H), 6.91 (s, 1H), 5.33 (s, 1H), 4.69-4.55 (m, 4H), 3.30 (s, 3H), 1.90-1.20 (m, 10H); LC-MS: m/z=407 (M+H)+.