Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH:12]=[CH:13][C:4]=2[NH:3][C:2]1=[O:14].[H-].[Na+].Br[CH2:18][CH3:19]>>[CH2:18]([N:3]1[C:4]2[CH:13]=[CH:12][C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=2[NH:1][C:2]1=[O:14])[CH3:19]
Reactant: O=c1[nH]c2ccc3ncccc3c2[nH]1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)[nH]c2c3cccnc3ccc21

Procedure:
3-Ethyl-quinolino[5,6-d]imidazolinone (1f) was prepared analogously by treatment of quinolino[5,6-d]imidazolinone with sodium hydride (1.1 eq.) and bromoethane (1.1 eq.), successively. Yield after column-chromatographic workup: 12%. Mp. 258-259° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]3=[N:14][C:15]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[N:16][CH:17]=[C:12]3[CH:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl>[CH3:24][N:22]1[CH:23]=[C:19]([NH:18][C:15]2[N:14]=[C:13]3[N:9]([CH2:8][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[N:7]=4)[N:10]=[CH:11][C:12]3=[CH:17][N:16]=2)[CH:20]=[N:21]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(F)n4)c3n2)cn1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCOCC5)n4)c3n2)cn1
Temperature: 180 °C
Yield: 64 %

Procedure:
1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (27 mg, 0.08 mmol) was dissolved in morpholine (0.6 ml) in a microwave tube under Nitrogen which was sealed and heated at 180° C. for 1 h. The mixture was diluted with DCM, washed with water and the water re-extracted with DCM. The combined organics were dried over Na2SO4, filtered and the solvent evaporated to give the title compound as a yellowish solid (20 mg, 64% yield). 1H NMR (d6-DMSO) δ 9.78 (br s, 1H), 8.91 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.52 (s, 1H), 7.46 (t, 1H), 6.68 (d, 1H), 6.28 (br s, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 3.62 (t, 4H), 3.35 (t, 4H); LC-MS method B, (ES+) 392.0, RT=6.84 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[Br:29])=[O:6].N1C=CC=CC=1.[C:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)#[N:40].C(=O)([O-])O.[Na+]>O1CCCC1>[C:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH:1][C:2]2[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=2)[C:5]([NH:7][C:8]2[C:9]([Br:29])=[CH:10][C:11]([C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([OH:20])[C:16]([F:19])([F:17])[F:18])=[CH:12][C:13]=2[Br:14])=[O:6])=[O:46])=[CH:43][CH:42]=1)#[N:40]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(C(=O)Nc2c(Br)cc(C(O)(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)Nc2cccc(C(=O)Nc3c(Br)cc(C(O)(c4cc(Cl)cc(Cl)c4)C(F)(F)F)cc3Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-N-{2,6-dibromo-4-[1-(3,5-dichloro-phenyl)-2,2,2-trifluoro-1-hydroxy-ethyl]-phenyl}-benzamide (Example I8) (0.147 mg, 0.24 mmol) in tetrahydrofuran (5 ml) were added successively pyridine (0.058 ml, 0.72 mmol) and 4-cyano-benzoyl chloride (48 mg, 0.29 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. Aqueous sodium hydrogen carbonate (saturated) was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1) to give the title compound.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[CH3:25]O>>[CH2:1]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:25])=[O:22])[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CO
Reactant: CCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: Cl
Product: CCCCCCCCCCCc1cc2ccc(C(=O)OC)cc2[nH]1

Procedure:
A solution of 2-(n-undecyl)indole-6-carboxylic acid (15.0 g) in methanol (200 ml) containing aqueous hydrochloric acid (10 ml of strength 36.5% w/v) was refluxed for 8 hours. The solution was concentrated in vacuo to about one half of its volume, diluted with diethyl ether (300 ml) and washed with water. The solution was dried over magnesium sulphate, then evaporated in vacuo and the residue was recrystallised from methanol to give methyl 2-(n-undecyl)indole-6-carboxylate (10.5 g), in the form of an off-white powder, m.p. 84°-86° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:36])[C:34]=1[F:35])[C:29](O)=[O:30].CCN=C=NCCCN(C)C>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:36])[C:34]=1[F:35])[C:29]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:30]
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(F)c(F)c(F)c4)C3)CC2)cn1

Procedure:
The title compound was prepared from 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3,4,5-trifluorobenzoic acid by EDCI coupling using the procedure described in Step C of Example 16.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1Br.[Cu](C#N)[C:23]#[N:24].N>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C:23]#[N:24]
Reactant: N#C[Cu]C#N
Reactant: N#Cc1ccc(N=Nc2ccc(OCCO)c(Br)c2)cc1
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1ccc(N=Nc2ccc(OCCO)c(C#N)c2)cc1
Temperature: 140 °C

Procedure:
15 g (4-(2-hydroxyethyloxy)-3-bromo-4′-cyanoazobenzene are dissolved in 25 ml hot DMF. 4.3 g copper cyanide are then added and the reaction mixture is stirred at 140° C. for 5–6 hours. This solution is added to approx. 500 ml of a 13% aqueous ammonia solution and the precipitate is filtered off. The precipitate is dissolved in hot dioxane. The solution is filtered off from the undissolved residue, the dioxane is evaporated off on a rotary evaporator and the product is purified by chromatography on silica gel in toluene/THF (½) and recrystallized once from ethanol. The yield of 4-(2-hydroxyethyloxy)-3,4′-dicyanoazobenzene is 4.5 g. M.p.=138° C.; max=356 nm (DMF).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[Cl:22][C:23]1[S:27][C:26]([CH2:28]O)=[N:25][N:24]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[Cl:22][C:23]1[S:27][C:26]([CH2:28][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[N:25][N:24]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: OCc1nnc(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C1N(Cc2nnc(Cl)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
To a solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.56 g, 1.99 mmol) and (5-chloro-1,3,4-thiadiazol-2-yl)methanol (0.30 g, 1.99 mmol) in anhydrous tetrahydrofuran (12.0 mL) was added tributylphosphine (0.60 g, 2.99 mmol) at 0° C. The reaction mixture was stirred for 15 min followed by the addition of N,N,N′,N′-tetramethylazodicarboxamide (0.51 g, 2.99 mmol). The reaction mixture was stirred at ambient temperature overnight, quenched with aqueous ammonium chloride (10.0 mL) and diluted with ethyl acetate (350 mL). The organic layer was washed with aqueous saturated sodium chloride (2×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, ½) to give the title compound (0.20 g, 24%) as a yellowish solid: mp 194-197° C.; 1H NMR (300 MHz, DMSO-d6,) δ 7.30 (dt, 1H), 7.20-7.12 (m, 2H), 7.05 (dt, 1H), 6.67 (s, 1H), 6.28 (s, 1H), 5.90 (s, 2H), 5.43 (d, 1H), 5.34 (d, 1H), 4.78 (d, 1H), 4.67 (d, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 168.3, 155.8, 155.4, 148.9, 142.2, 141.9, 132.2, 129.4, 124.2, 124.0, 120.1, 109.8, 103.7, 101.9, 93.8, 80.1, 67.5, 57.9, 25.6; MS (ES+) m/z 414.2 (M+1), 416.2 (M+1).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=1)([CH3:5])[CH3:4])#[N:2].S(=O)(=O)(O)[OH:22].N>>[NH2:2][C:1]([C:3]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:12][C:8]=2[CH:7]=1)([CH3:5])[CH3:4])=[O:22]
Reactant: CC(C)(C#N)c1ccc2nc(-c3ccncc3)[nH]c2c1
Reactant: O=S(=O)(O)O
Agent: N
Product: CC(C)(C(N)=O)c1ccc2nc(-c3ccncc3)[nH]c2c1

Procedure:
3.7 g. of the 5-(2-cyanopropan-2-yl)-2-(4-pyridinyl)benzimidazole (prepared in Example 15) are stirred for 3 hours at 50° C. in 40 ml. 80% sulphuric acid, the compound thereby slowly going into solution. The reaction mixture is then poured on to ice, rendered alkaline with ammonia, filtered off with suction and recrystallised from ethanol. There are obtained 2.4 g. (61% of theory) of the title compound in the form of colourless crystals; m.p. 274°-276° C.
Reaction SMILES: [ClH:1].C(O[N:5]=[CH:6][C:7]1[CH:22]=[CH:21][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=1)C.[Cl-].[NH4+:24].N>C(O)C>[ClH:1].[C:6]([C:7]1[CH:22]=[CH:21][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=1)(=[NH:5])[NH2:24]
Reactant: CCON=Cc1ccc(OCCCCC(=O)OCC)cc1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)CCCCOc1ccc(C(=N)N)cc1
Temperature: 25 °C
Yield: 106.1 %

Procedure:
A mixture of ethyl 5-[4-{1-(ethoxy)iminomethyl}phenoxy]valerate hydrochloride (28.2 g), ammonium chloride (4.8 g), ethanol solution of ammonia (42 ml) in ethanol (300 ml) was stirred and refluxed for 15 hours. After cooled to room temperature, the mixture was filtrated, and the filtrate was evaporated in vacuo, and the resulting precipitate was washed with diethyl ether to give ethyl 5-(4-amidinophenoxy)valerate hydrochloride (27.28 g).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]([O:6][CH:7]([Cl:12])[C:8]([Cl:11])([Cl:10])[Cl:9])=[O:5]>ClCCl>[CH3:1][NH:2][C:4](=[O:5])[O:6][CH:7]([Cl:12])[C:8]([Cl:11])([Cl:10])[Cl:9]
Reactant: CN
Reactant: O=C(Cl)OC(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)OC(Cl)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
34.7 ml (0.4 mmol) of methylamine (in 40% strength aqueous solution) are added dropwise to a solution maintained at 0° C. of 49.4 g (0.2 mole) of 1,2,2,2-tetrachloroethyl chloroformate in dichloromethane (150 ml). The mixture is then stirred for 2 hours at room temperature. The organic phase is washed with 2×100 ml of water and dried over magnesium sulphate.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([O:27]C)=[C:17]([CH3:29])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>>[CH2:1]([C:8]1[S:9][C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]([OH:27])=[C:17]([CH3:29])[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc(-c2ccccc2)c1O
Yield: 76.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(5-methyl-6-methoxy-biphen-3-yl)-methanone (1.68 g, 4.09 mmol) and 1M boron tribromide/CH2Cl2 (8.58 mL). Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.29 g (80%) of the title compound. 1H NMR (DMSO-d6) δ 1.83 (s, 3 H), 2.17 (s, 3 H), 2.25 (s, 3 H), 3.85 (s, 2 H), 7.07-7.10 (m, 2 H), 7.14-7.26 (m, 3 H), 7.33-7.43 (m, 6 H), 7.54 (d, 1 H), 9.31 (s, 1 H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:40][CH:41]=3)[N:23]=2)(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Phenyl chloroformate (0.256 mL, 2.04 mmol) was added dropwise to 4-[4-[(4-chlorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (850 mg, 1.85 mmol) and sodium hydrogen carbonate (233 mg, 2.78 mmol) in dioxane (20 mL) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2×100 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane, to give the desired material as a white solid (955 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:7][C:8]12[CH2:9][CH2:10][CH:11]3[CH:20]([CH2:19][CH2:18][C:17]4[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=43)[CH:21]1[CH2:22][CH2:23][C:24]2=[CH2:1]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCC2C3CCc4cc(O)ccc4C3CCC12C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
Potassium tert-butoxide (220 mg, 1.96 mmol) was added to dry THF (5 ml) and stirred for 10 minutes to complete dissolution of the salt. Methyl triphenylphosphonium bromide (700 mg, 1.96 mmol) was added portionwise to the salt solution. Estrone (500 mg, 1.85 mmol) was dissolved in THF (5 ml) and added dropwise via a syringe to the bright yellow solution. After stirring at room temperature for 2 h, the reaction was heated at reflux overnight. The reaction was cooled, water added (10 ml) and the mixture extracted using ethyl acetate (3×10 ml). The combined organic fractions were combined, washed with water (2×10 ml) and brine (10 ml), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (SiO2 hexane:ethyl acetate 9:1) and recrystallisation from toluene/hexane afforded alkene 11 as a white crystalline solid (53 mg, 0.198 mmol, 11%). m.p. 130-132° C. (lit. m.p. 134-137° C.). δH (CDCl3) 0.82 (3H, s CH3), 1.20-1.62 (6H, m, alkyl H), 1.78-1.85 (1H, m, alkyl H), 1.90-1.99 (2H, m, alkyl H), 2.16-2.38 (3H, m, alkyl H), 2.50-2.59 (1H, m, alkyl H), 2.78-2.92 (2H, m, alkyl H), 4.50 (1H, s, OH), 4.67 (2H, t, J=2.0, olefinic H), 6.57 (1H, d, J=2.7, ArH-4), 6.63 (1H, dd, J=8.6, 2.7, ArH-2), 7.17 (1H, d, J=8.6, ArH-1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[Br:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
A solution of triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (114 mg, 0.64 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-aminothiazole (117 mg, 1.17 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (214 mg, 88%) as a yellow solid: mp 106-107° C.; EI-HRMS m/e calcd for C18H21BrN2O3S2 (M+) 456.0177, found 456.0175.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH3:38])[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH3:38])(=[O:36])=[O:35])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: Cc1ccccc1S(N)(=O)=O
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2C)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and o-toluenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (37%); 1H NMR (CD3OD) δ 11.63 (br s, 1H), 7.54 (d, J=15.7 Hz, 2H), 7.39–7.09 (m, 15H), 6.87 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 6.41 (d, J=15.7 Hz, 1H), 3.02–2.73 (s, 3H), 2.37 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:31])[C:8]([NH:29][NH2:30])([CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([O:19]CC)=O)=[C:12]([O:22][C:23]([O:25]CC)=O)[CH:11]=1)(=[O:3])[CH3:2].C[C:33]([CH3:38])([CH3:37])[C:34](Cl)=O>>[C:1]([O:4][CH2:5][O:6][C:7](=[O:31])[C@:8]([NH:29][NH2:30])([CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:19])[C:33]([CH3:38])([CH3:37])[CH3:34])=[C:12]([O:22][C:23](=[O:25])[C:8]([CH3:28])([CH3:9])[CH3:7])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCOC(C)=O)cc1OC(=O)OCC
Product: CC(=O)OCOC(=O)[C@](C)(Cc1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1)NN

Procedure:
Following the procedure for preparation of compound 101, and substituting ethyl chloroformate with 2,2-dimethylpropionyl chloride, provided the title compound. 1H NMR (CD3OD, 400 MHz): δ 1.33 (s, 9H), 1.34 (s, 9H), 1.46 (s, 3H), 2.12 (s, 3H), 3.08 (dd, 2H), 5.83 (dd, 2H), 7.05–7.12 (m, 3H). MS (ESI) m/z 467.35 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH2:2][O:1][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=1)=[O:29]
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: Cc1ccc(N=C=O)cc1
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(C)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-(3-(hydroxymethyl)-4-methoxybenzyl]malonate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([C:20]([CH3:22])=[CH2:21])[CH2:8][CH2:9]/[C:10](/[CH3:19])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]I.[Mg].CI.[Cl-].[NH4+]>CCOCC>[C:1]([Si:5]([CH3:23])([CH3:24])[O:6][CH:7]([C:20]([CH3:22])=[CH2:21])[CH2:8][CH2:9]/[C:10](/[CH3:19])=[CH:11]/[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][C:16]([OH:17])=[CH2:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]I
Reactant: C=C(C)C(CC/C(C)=C/CCC(C)=CC=O)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: C=C(O)C=C(C)C=C/C=C(\C)CCC(O[Si](C)(C)C(C)(C)C)C(=C)C
Reaction time: 2 h

Procedure:
A solution of 7.3 g of (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrienal in 10 ml of ether is added dropwise at -20° to a methylmagnesium iodide solution prepared from 0.56 g of magnesium shavings and 3.1 g of methyl iodide in 80 ml of ether. After stirring at -20° for 2 hours the reaction mixture is poured into a mixture of ice and saturated ammonium chloride solution and extracted twice with ether. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The oil which remains behind as the residue is chromatographed on silica gel with hexane-ethyl acetate-triethylamine 90:10:0.1, whereby (7E)-11-(tert.-butyldimethylsiloxy)-4,8,12-trimethyl-3,7,12-tridecadien-trien-2-ol is obtained as a colourless oil. NMR (250 MHz, CDCl3): 5.2 (d, J=8 H-C(3)); 5.1 (t, J=6.5, H-C(7)); 4.84 and 4.75 (2m, 2H-C(13)); 4.57 (m, H-C(2)); 4.0 (t, J=6.5, H-C(11)); 2.25-1.4 (m, 4CH2, 3CH3); 1.22 (d, J=6.5, 3H-C(1)); 0.89 (s, SiC(CH3)3); 0.04 and 0.0 (2s, Si(CH3)2).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=1.[OH-].[Na+]>COCCO>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([NH:30][C:31]2[N:33]=[CH:12][C:9]3[CH2:8][CH2:7][C:5]4[N:6]=[C:2]([CH3:1])[S:3][C:4]=4[C:10]=3[N:32]=2)=[CH:26][CH:25]=1
Reactant: N=C(N)Nc1ccc(Cl)nc1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(Cl)nc3)ncc1CC2
Temperature: 100 °C
Yield: 16 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 0.76 mmol), N-(6-chloro-pyridin-3-yl)-guanidine nitrate (196 mg, 0.84 mmol), NaOH (34 mg, 0.84 mmol) and 2-methoxyethanol (2 mL) was heated at 100° C. for 24 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the pure title product as a white solid (40 mg, 16%): mp 252-253° C. Anal. RP-HPLC: tR 16.8 min (10-70% MeCN, purity 92%). 1H-NMR (DMSO-d6) δ 9.98 (s, 1H, NH), 8.90 (d, 1H, J 2.9, Ph-H), 8.44 (s, 1H, Py-H), 8.29 (dd, 1H, J 8.7, 2.4, Ph-H), 7.50 (d, 1H, J 8.7, Ph-H), 3.10 (m, 4H, CH2—CH2), 2.82 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 169.08, 159.26, 158.47, 156.22, 155.35, 141.23, 139.69, 137.05, 128.55, 127.52, 123.55, 117.05, 24.60, 23.07, 19.39. MS (ESI+): m/z 330.06 (M+H)+.