Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)O[CH2:4][CH2:3][O:2]1.[Cl:7][C:8]1[C:13]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[N:20]([CH:24]([CH3:26])[CH3:25])[N:21]=[CH:22][N:23]=3)[N:18]=2)=[CH:12][N:11]=[C:10]([O:27][CH3:28])[CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([O:27][CH3:28])[N:11]=[CH:12][C:13]=1[C:14]1[N:15]([CH2:4][CH2:3][OH:2])[CH:16]=[C:17]([C:19]2[N:20]([CH:24]([CH3:25])[CH3:26])[N:21]=[CH:22][N:23]=2)[N:18]=1
Reactant: O=C1OCCO1
Reactant: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)c[nH]2)cn1
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)cn2CCO)cn1
Temperature: 130 °C
Yield: 75.6 %

Procedure:
To warmed ethylene carbonate (34 g) was added 4-chloro-5-[4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine (8.74 g, 27.4 mmol) and the mixture heated at 130° C. for 3 h. The cooled reaction mixture was diluted with DCM and loaded onto silica (150 g). The silica was washed with DCM then 5% methanol in DCM. Methanolic fractions were combined and concentrated in vacuo to give the title compound as a brown foam (7.52 g, 75%). LCMS RT=2.65, [M+H]+=363/365. 1H NMR 400 MHz (CDCl3) δ: 8.27 (1 H, s), 8.02 (1 H, s), 7.85 (1 H, s), 6.93 (1 H, s), 5.98-5.82 (1 H, m), 4.00 (5 H, m), 3.88 (2 H, t, J=5.11 Hz), 1.51 (6 H, d, J=6.62 Hz).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([O:20]C)=O)([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7]>C1COCC1>[CH3:4][O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18](=[O:20])[N:2]([CH3:3])[CH3:1])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7]
Reactant: COC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)C12CC3CC(C1)CC(C(=O)N(C)C)(C3)C2
Yield: 80 %

Procedure:
1 mmole of 1,3-bis(methozxycarbonyl)adamantane obtained by the method of Example 84 was dissolved in 30 ml of THF. To the mixture, 0.5 mmole of dimethylamine and 0.1 mmole of aluminum chloride anhydride AlCl3 was added and reacted for 6 hours at 80° C. As a result, The conversion of 1,3-bis(methoxycarbonyl)adamantane was 90%, and 1-methoxycarbonyl-3-(N,N-dimethylcarbamoyl)adamantane (yield 80%) was formed.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:19][C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:22][CH:21]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc(C(=O)OC(C)(C)C)cc3)C2=O)cc1

Procedure:
The title compound 28p was prepared from compound 2 (75 mg, 0.30 mmol), tert-butyl 4-(bromomethyl)benzoate (106 mg, 0.39 mmol) and potassium carbonate (83 mg, 0.60 mmol) in a manner similar to that described for 28d in 96.4% (127 mg) yield as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]1[CH:62]=[CH:61][CH:60]=[CH:59][C:43]=1[CH2:44][N:45]1[CH2:49][CH2:48][N:47]([C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51](O)=[O:52])[C:46]1=[O:58].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:51](=[O:52])[C@@H:50]([N:47]1[CH2:48][CH2:49][N:45]([CH2:44][C:43]2[CH:59]=[CH:60][CH:61]=[CH:62][C:42]=2[O:41][CH3:40])[C:46]1=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2OC)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 75A (0.020 g, 0.062 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.024 g, 59% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 1 H), 1.38 (m, 1 H), 1.54 (m, 2 H), 2.33 (m, 1 H), 2.83 (m, 5 H), 3.18 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.83 (m, 4 H), 4.25 (m, 4 H), 4.53 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.93 Hz, 1 H), 6.95 (t, J=6.99 Hz, 1 H), 7.18 (m, 11 H), 7.45 (d, J=9.19 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:8])[C:4](=[O:7])[CH2:5][Br:6].[CH2:9]([O:11]C(OCC)OCC)[CH3:10].S(=O)(=O)(O)O.[CH3:24][CH2:25]CCCC>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([O:11][CH2:9][CH3:10])([O:8][CH2:24][CH3:25])[C:4](=[O:7])[CH2:5][Br:6]
Reactant: O=C(CBr)C(=O)CBr
Reactant: CCCCCC
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(CBr)(OCC)C(=O)CBr
Temperature: 25 °C
Reaction time: 14 h
Yield: 84 %

Procedure:
A mixture of 40 g (0.164 mol) of 1,4-dibromo-2,3-butanedione, 60 ml (0.36 M) of triethylorthoformate, and 2 ml of concentrated sulfuric acid was stirred at room temperature for 14 hours, then diluted with 600 ml of chloroform, and washed successively with 100 ml portions of water, 0.5 N hydrochloric acid and saturated sodium chloride solution. The organic solution was dried over anhydrous sodium sulfate filtered, and evaporated leaving an oil. The oil was taken up into 300 ml of hexane and filtered to remove some insoluble material. The hexane filtrate was cooled in a dry-ice/acetone bath, and the resulting precipitate was collected by filtration and dried to give 44 g (84%) of 1,4-dibromo-2,2-diethoxy-3-butanone as a white crystalline solid, mp 40°-41.5°; nmr (CDCl3) (δ): 4.50 (s, 2H); 3.6-3.2 (m, 6H); 1.22 (t, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=2)[O:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH2:14][OH:15])=[CH:2]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:22][S:23]([O:15][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([CH2:10][O:9][C:8]2[CH:19]=[CH:20][CH:21]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)[CH:12]=1)(=[O:25])=[O:24]
Reactant: OCc1cccc(COc2cccc(-c3ccsc3)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccc(COc2cccc(-c3ccsc3)c2)c1

Procedure:
104 mg of 3-[3-(3-thienyl)phenoxymethyl]benzyl alcohol was dissolved in 1 ml of ethyl acetate, and 45 microliters of methanesulfonyl chloride and 88 microliters of triethylamine were added with ice cooling and stirring. The reaction mixture was stirred for 1 hour. The precipitate was removed by filtration, and the organic layer was separated, then dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated to give 3-[3-(3-thienyl)phenoxymethyl)benzyl methanesulfonate as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][NH:6][CH2:5][C:4]2[NH:8][C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])=[N:10][C:3]1=2.C(O)(=O)C.[Na].[CH3:41][C:42]([CH3:44])=O>CN(C=O)C>[CH:42]([N:6]1[CH2:7][C:2]([CH3:35])([CH3:1])[C:3]2[N:10]=[C:9]([C:11]3[C:12]([CH3:34])=[CH:13][C:14]([CH3:33])=[C:15]([CH:32]=3)[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)=[O:17])[NH:8][C:4]=2[CH2:5]1)([CH3:44])[CH3:41]
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3(C)C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CC(C)=O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2nc3c([nH]2)CN(C(C)C)CC3(C)C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
4-(1-(5-(7,7-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (0.12 g, 0.26 mmol) (intermediate prepared in the synthesis of compound 451), DMF (4 mL), acetic acid (69 μL, 1.21 mmol), sodium triacetoxyborohydide (0.11 g, 0.52 mmol) and acetone (0.50 mL, 6.8 mmol) were mixed and stirred at room temperature for 2 hours. The reaction was carefully quenched with water (10 mL) and the mixture was extracted with ethyl acetate (60 mL) and the organics was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by preparative TLC (DCM/10% MeOH) followed by a second preparative TLC (ethyl acetate/5% MeOH) to obtain the title compound as a white powder (4.1 mg, 8.1%). m/z (ES+) 510 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:29])[C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][NH:31][S:32]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)(=[O:34])=[O:33]>>[ClH:1].[CH3:30][NH:31][S:32]([CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:43][C:2]2[N:7]=[C:6]([N:8]([C:9]3[CH:28]=[CH:27][C:12]4[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)=[N:15][C:11]=4[CH:10]=3)[CH3:29])[CH:5]=[CH:4][N:3]=2)=[CH:41][CH:42]=1)(=[O:33])=[O:34]
Reactant: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Product: CNS(=O)(=O)CCc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccc(OC)cc3)n4C)n2)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-methoxy-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (82 mg, 0.20 mmol) and 2-(4-amino-phenyl)-ethanesulfonic acid methylamide (43 mg, 0.20 mmol) as a white solid (105 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ 10.18 (br s, 1H), 9.46 (br s, 1H), 7.88 (d, J=6.6 Hz, 1H), 7.54-7.62 (m, 3H), 7.40-7.47 (M, 3H), 7.18-7.26 (M, 3H), 7.01 (M, 1H), 6.92 (d, J=8.4 Hz, 2H), 5.83 (d, J=6.3 Hz, 1H), 4.68 (d, J=5.4 Hz, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 3.48 (s, 3H), 3.23-3.28 (m, 2H), 2.87-2.93 (M, 2H), 2.60 (d, J=4.8 Hz, 3H). MS (ESI) m/z=587 [M+H]+.
Reaction SMILES: [Cl:1][O-].[Na+].[Cl:4][C:5]1[C:15]([Cl:16])=[C:14]([C:17]([C:19]2[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][CH:20]=2)=[O:18])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.CN(C)C=O.O>[Cl:4][C:5]1[C:15]([Cl:16])=[C:14]([C:17]([C:19]2[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=2[Cl:1])=[O:18])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCn1nccc1C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: [O-]Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc(Cl)c1C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.7 g of an aqueous 10% sodium hypochlorite solution are added dropwise to a solution of 2.36 g of [2,3-dichloro-4-(1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid in a mixture of 50 ml of acetic acid and 20 ml of dimethylformamide, and the mixture is stirred at room temperature for 30 minutes. A solution of 2.0 g of sodium thiosulfate in 5 ml of water is added to the reaction mixture to decompose excess sodium hypochloride, and the mixture is evaporated to remove solvent. The residue (oil) is dissolved in water, and the solution is adjusted to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is crystallized from a mixture of ethyl acetate and hexane to give 2.19 g of [2,3-dichloro-4-(4-chloro-1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]=[C:47]=[O:48]>CN(C)C=O>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH:46][C:47]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)=[O:48]
Reactant: O=C=Nc1ccccc1F
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(C(=O)Nc5ccccc5F)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
2-Isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (220 mg, 0.55 mmol) was dissolved in N,N-dimethylformamide (2.0 mL) at room temperature. To this solution was added N,N-diisopropylethylamine (143.2 mg, 1.1 mmol) followed by o-fluorophenylisocyanate (75.4 mg, 0.55 mmol). The resulting mixture was stirred at room temperature overnight, concentrated in vacuo and the residue purified by preparative reverse-phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (92.6 mg, 0.12 mmol, 22%). (m/z): [M+H]+ calcd for C30H39FN6O2 535.32. found 535.2. Retention time (anal. HPLC: 2-65% MeCN/H2O over 4 min)=2.09 min.
Reaction SMILES: [CH2:1]([C:4]1([CH2:16][CH2:17][CH3:18])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[CH:15])[CH:12]=2)[S:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.I[C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:16]([C:4]1([CH2:1][CH2:2][CH3:3])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[C:15][C:27]3[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=3)[CH:12]=2)[S:7][CH2:6][CH2:5]1)[CH2:17][CH3:18]
Reactant: C#Cc1ccc2c(c1)C(CCC)(CCC)CCS2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)CCSc2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A mixture of 0.338 g (1.47 mmol) of 4,4-dipropylthiochroman-6-yl)acetylene (Compound 31), 24 mg, (0.13 mmol) of copper (I) iodide, and 2.54 g (25 mmol of triethylamine were degassed with argon for 15 minutes. To the suspension was added 0.57 g (2.07 mmol) of ethyl 4-iodobenzoate (Compound 22) and then 0.12 g (0.17 mmol) of bis(triphenylphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55° C. for 16 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CO>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 107.3 %

Procedure:
A cooled (0° C.) solution of compound 55A (510.1 mg, 1.51 mmol) and imidazole (516 mg, 7.58 mmol) in dry DMF (2.6 mL) was treated with 97% tert-butyldimethylsilyl chloride (572 mg, 3.68 mmol), stirred at 0° C. for 5 min then at rt for 24 h. Methanol (3.5 mL) was added and the solution stirred at rt for another 24 h. The mixture was partitioned between 10% citric acid (5.3 mL) and EtOAc (3×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting syrup was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (732.3 mg, 100%) as a white solid, mp 123-125° C. HPLC: 3.38 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=9.30 min (98.6%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 452 [M+H]+.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]1[CH3:10])(=O)C.[O:11]1CC[CH2:13][CH2:12]1>>[C:12]([C:8]1[NH:4][C:5]([CH3:10])=[N:6][C:7]=1[CH3:9])(=[O:11])[CH3:13]
Reactant: C1CCOC1
Reactant: CC(=O)n1cc(C)nc1C
Product: CC(=O)c1[nH]c(C)nc1C
Yield: 41 %

Procedure:
A solution of 6.9 g (0.05M) of 1-acetyl-2,4-dimethylimidazole in 700 ml of dry tetrahydrofuran was photolyzed in a quartz flask with a short wave ultraviolet light source (254 nm) for 40 hours. The tetrahydrofuran solution was concentrated in vacuo to give an oil which was chromatographed on silica gel using 5% methanol in chloroform as eluent to give 2.8 g (41%) of 5-acetyl-2,4-dimethylimidazole as a white solid, mp 83°-87°. Recrystallization from isopropyl ether gave analytically pure material, mp 87°-88°. nmr (CDCl3) (δ): 2.53 (s, 6H); 2.40 (s, 3H). Anal. Calcd. for C7H10N2O: C, 60.85; H, 7.30; N, 20.27; found: C, 60.66; H, 7.26; N, 20.09.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1.N1C=CC=CC=1>ClCCl.CN(C)C=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])=[O:9])=[N:22][CH:23]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of 5-methyl-2-nitrobenzoic acid (1 g, 5.52 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.964 ml, 11.04 mmol) and a few drops of dimethylformamide. The mixture was stirred at r.t. for 2 hrs. After the evaporation of the solvent, the residue was dissolved in dichloromethane (5 ml). 2-amino-5-chloropyridine (852 mg, 6.62 mmol) and pyridine (1.34 ml, 16.56 mmol) were added to the solution. The mixture was stirred at r.t. overnight. After the evaporation of the solvent, the crude residue was purified by silica gel column chromatography using solvent system 25% ethyl acetate in hexane as eluent to give N-(5-chloro(2-pyridyl))(5-methyl-2-nitrophenyl)carboxamide as a solid (1.48 g, 92%). MS found for C13H10ClN3O3 M+=291, (M+2)+=293.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21]([CH3:23])=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:25])[CH:4]=[CH:5][C:6](=[O:24])[CH:7]=1.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:29][CH2:23][S:21][C:15]1[C@:16]2([CH2:18][C@H:19]([OH:20])[C@@:2]3([F:1])[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:25])[CH:4]=[CH:5][C:6](=[O:24])[CH:7]=4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:17])(=[O:28])[CH3:27]
Reactant: CS(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 110 °C

Procedure:
A mixture of 1.5 g of 9-fluoro-11β-hydroxy-17-(methylsulfinyl)androsta-1,4,16-trien -3-one, 70 ml of acetic anhydride and 2 g of fused sodium acetate is heated at 110° C. under nitrogen for 2 hours. The acetic anhydride is partially removed by distillation under vacuum and the resulting slurry is diluted with 1:1 chloroform-water. The organic layer is separated, washed with diluted sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in 4:1 chloroform-hexane and chromatographed on a 40 g-silica gel column. Elution with 1:4 hexane-chloroform gives 940 mg of slightly impure material. Two crystallizations from acetone-hexane give 350 mg of the title compound, melting point 193°-194° C., with consistent spectral data.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH:33]1[CH2:35][CH2:34]1)[C:6](=[O:32])[C@@H:7]([NH:22][S:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH2:8][C:9]([NH:11][CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([NH2:21])=[NH:20])[CH2:14]1)=[O:10].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([S:43](Cl)(=[O:45])=[O:44])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([OH:44])(=[O:29])[CH3:31].[NH2:20][C:19](=[NH:21])[N:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([CH2:12][NH:11][C:9](=[O:10])[CH2:8][C@H:7]([NH:22][S:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)(=[O:25])=[O:24])[C:6]([N:5]([CH:33]2[CH2:35][CH2:34]2)[CH2:4][CH2:3][NH:2][S:43]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)(=[O:45])=[O:44])=[O:32])[CH2:14]1
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Reactant: N=C(N)N1CCC[C@@H](CNC(=O)C[C@H](NS(=O)(=O)N2CCOCC2)C(=O)N(CCN)C2CC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)O
Product: CN1CCN(S(=O)(=O)NCCN(C(=O)[C@H](CC(=O)NC[C@@H]2CCCN(C(=N)N)C2)NS(=O)(=O)N2CCOCC2)C2CC2)CC1

Procedure:
330 mg of (S)-N1-(2-amino-ethyl)-N4-[(S)-1-(amino-imino-methyl)-piperidin-3-ylmethyl]-N1-cyclopropyl-2-morpholin-4-ylsulphonylamino-succinamide hydrochloride are stirred at room temperature for 20 hours together with 162 mg of 4-methyl-piperazin-1-ylsulphonyl chloride and 0.49 ml of Hunig's base in 8 ml of methylene chloride. The reaction mixture is chromatographed over silica gel with ethyl acetate/acetone/glacial acetic acid/water 2:2:2:1. 14.9.1 mg of pure crystalline (S)-N4-[(S)-1-(amino-imino-methyl)-piperidin-3-ylmethyl]-N1-cyclopropyl-N1-[2-(4-methyl-piperazin-1-ylsulphonylamino)-ethyl]-2-morpholin-4-ylsulphonylamino-succinamide acetate (1:2), MS (ISP): 665.6 (M+H) and 333.7 (M+2H), are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[Sn](CCCC)(CCCC)CCCC>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:29]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[F:23]
Reactant: COc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1F
Product: COc1ccc(-c2nncc(-c3ccc(F)c(-c4ccncc4F)c3)n2)cc1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(4-methoxyphenyl)-[1,2,4]triazine (from Example 9 below) (150 mg, 0.42 mmol) was coupled to 3-fluoro-4-tributylstannylpyridine (170 mg, 0.43 mmol) using the method of Example 6 to give 5-[4-fluoro-3-(3-fluoro-pyridin-4-yl)phenyl]-3-(4-methoxyphenyl)-[1,2,4]triazine, crystallised from hot toluene (70 mg): δH (400 MHz, d6-DMSO) 3.88 (3H, s), 7.16 (2H, d, J 8.9 Hz), 7.69-7.77 (2H, m), 8.53 (2H, d, J 8.9 Hz), 8.63-8.67 (3H, m), 8.79 (1H, m), 10.05 (1H, s); m/z (ES+) 377.