Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:36][C:37]1[C:38]([CH2:43]Br)=[CH:39][CH:40]=[CH:41][CH:42]=1>C(Cl)Cl>[Cl:22][C:21]1[C:16]2[C:15](=[O:23])[N:14]3[CH2:24][CH2:25][C@H:13]3[C:12]3[N:11]([CH:10]=[N:9][C:8]=3[C:5]3[N:4]=[C:3]([CH2:2][N:1]4[CH2:43][C:38]5[C:37](=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36]4)[O:7][N:6]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1ccccc1CBr
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN4Cc5ccccc5C4)n3)c2[C@@H]2CCN12
Yield: 33.8 %

Procedure:
3.56 g (10 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 15 ml of methylene chloride, 8.6 ml (50 mmol) of N-ethyldiisopropylamine and 2.64 g (10 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 20 hours. The reaction solution was washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on 500 g of silica gel while eluting with methylene chloride/methanol 19/1. There were obtained 1.55 g (33%) of (S)-8-chloro-12,12a-dihydro-1-(5-isoindolin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 218°-222°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:11][CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[O-]CC.[Na+]>C(O)C>[Cl:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:11][CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=2)=[CH:15][CH:14]=1
Reactant: Cc1cc(=O)n2ccsc2n1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cc(/C=C/c2ccc(Cl)cc2)nc2sccn12
Temperature: 25 °C

Procedure:
To a stirred solution of Step 1 intermediate (200 mg, 1.206 mmol) in ethanol (30 ml) was added 4-chlorobenzaldehyde (253 mg, 1.795 mmol) followed by sodium ethoxide (122 mg, 1.795 mmol) in ethanol at room temperature. The reaction mixture was heated to reflux for 12 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue obtained was partitioned between chloroform (100 ml) and water (50 ml). The organic layer was washed with brine (100 ml), dried (Na2SO4) and concentrated to afford a crude product which was purified by silica gel column chromatography using 2% acetone in chloroform to give 59 mg of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 6.25 (s, 1H), 6.87 (d, J=15.6 Hz, 1H), 6.94 (d, J=4.8 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.73 (d, J=15.6 Hz, 1H), 7.90 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 289.37 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]1[C:6]([OH:11])([C:7]([F:10])([F:9])[F:8])[O:5][N:4]=[C:3]1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=1[F:20].[C:21](OC(=O)C)(=[O:23])[CH3:22]>S(=O)(=O)(O)O>[Cl:1][CH:2]1[C:6]([O:11][C:21]([CH3:22])=[O:23])([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=[C:3]1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=1[F:20]
Reactant: CC(=O)OC(C)=O
Reactant: OC1(C(F)(F)F)ON=C(c2cc(F)c(Cl)cc2F)C1Cl
Agent: O=S(=O)(O)O
Product: CC(=O)OC1(C(F)(F)F)ON=C(c2cc(F)c(Cl)cc2F)C1Cl
Temperature: 160 °C

Procedure:
One drop of concentrated sulfuric acid was added to 3.2 g of 4-chloro-3-(4'-chloro-2',5'-difluorophenyl)-5-hydroxy-5-trifluoromethylisoxazoline in 45 ml of acetic anhydride. The mixture was subsequently briefly heated to 160° C. After cooling, the reaction mixture was then concentrated under reduced pressure. The oily crude product was purified by silica gel chromatography (eluent: methylene chloride). Yield: 2.5 g; oil.
Reaction SMILES: [CH2:1]([Si:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:16](B(O)O)=[C:15]([F:23])[C:14]([F:24])=[CH:13][C:12]=2[CH2:11]1)[CH2:2][CH2:3][CH3:4].Br[CH:28]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([Si:5]([CH3:26])([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([F:24])=[C:15]([F:23])[C:16]=2[C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:37][CH:36]=2)[CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Si](C)(C)CCCCC1CCc2c(cc(F)c(F)c2B(O)O)C1
Reactant: CCCCCCC(Br)CCCc1ccccc1
Product: CCCCCCCCCCc1ccc(-c2c(F)c(F)cc3c2CCC(CCCC[Si](C)(C)CCCC)C3)cc1

Procedure:
From 6-[4-(butyldimethylsilanyl)butyl]-2,3-difluoro-5,6,7,8-tetrahydronaphthalene-1-boronic acid and 4-bromodecylbenzene by means of the Suzuki coupling.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@@H:26]([O:29][CH3:30])[CH2:25][CH2:24]2)[CH:3]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@H:23]3[CH2:28][CH2:27][C@@H:26]([O:29][CH3:30])[CH2:25][CH2:24]3)[C:10]=2[C:17]=1[CH3:18])=[O:21]
Reactant: CN(C)CCCN
Reactant: CO[C@H]1CC[C@@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)CC1
Product: CO[C@H]1CC[C@@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCCN(C)C)c(C)c23)CC1

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[4-fluoro-2-(cis-4-methoxy-cyclohexyloxy)phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 42 μl N,N-dimethyl-1,3-propanediamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11])([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[C:5]=1[OH:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a solution of 3-nitrobenzene-1,2-diol (2.78 g) and 3,4-dihydro-2H-pyrane (1.81 g) in benzene (39 ml) was added p-toluenesulfonic acid monohydrate (5 mg) at ambient temperature, and the mixture was stirred for 24 hours. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-methanol) and crystallized with n-hexane to give 2-nitro-6-(tetrahydropyran-2-yloxy)phenol (2.32 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][N:19]([CH2:26][CH2:25][C:24]([O:28][CH3:29])=[O:27])[CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1CNCCC1(F)c1cccc(OCc2ccccc2)c1
Reactant: C=CC(=O)OC
Agent: Cl
Product: COC(=O)CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)C(C)C1
Yield: 81 %

Procedure:
This compound was prepared from 4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidine hydrochloride and methyl acrylate as described in Step 1 of Example 4 in 81% yield.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:46])[CH2:30][CH2:31][N:32]([S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:46][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH2:43][CH2:44][CH3:45])(=[O:42])=[O:41]
Reactant: CCCS(=O)(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCCS(=O)(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-propylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H34N4O5S
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.8 %

Procedure:
To a solution of 3,5-dichlorophenol (5.0 g, 30 mmol) and CH2Cl2 (60 mL) were added tert-butyldimethylsilyl chloride (5.54 g, 36 mmol), N,N-diisopropylethylamine (8.0 mL, 46 mmol), and a catalytic amount of 4-dimethylaminopyridine. The initially exothermic solution was stirred at ambient temperature for 6 h then diluted with CH2Cl2 (40 mL). The mixture was washed consecutively with 10% aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the title compound as a pale yellow liquid (8.8 g, 100%). 1H NMR (CDCl3) δ 6.98 (s, 1H), 6.72 (s, 2H), 0.98 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[N:10][CH:11]=2.[SiH](CC)(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:9]2[N:8]=[C:7]3[C:12]([N:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[NH:6]3)=[CH:11][N:10]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Cn2c(-c3ccncc3)nc3cnc(Nc4ccc(F)cc4)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(Nc2ncc3nc(-c4ccncc4)[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A solution of 46 mg (0.1 mmol, 1.0 eq.) of 9-(2,4-dimethoxybenzyl)-N-(4-fluorophenyl)-8-(pyridin-4-yl)-9H-purin-2-amine (I-17) in 0.6 mL of methylene chloride and 2.4 mL of TFA was stirred at room temperature for 4 h. A portion of 1 mL of Et3SiH was added and the resulting reaction mixture stirred at room temperature for an additional 1 h. The volatiles were removed in vacuo and the residue purified by semi-preparative HPLC to provide 7.3 mg (24%) of N-(4-fluorophenyl)-8-(pyridin-4-yl)-9H-purin-2-amine (I-18).
Reaction SMILES: [OH:1][CH:2]1[C@H:15]([S:16][CH2:17][C:18]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@@H:5]([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:28])[CH2:3]1.[BH4-].[Na+]>>[OH:28][CH:4]1[CH2:3][CH:2]([OH:1])[C@H:15]([S:16][CH2:17][C:18]2([O:24][CH2:25][CH2:26][O:27]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:5]1[CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCCCC1(CS[C@H]2C(O)CC(=O)[C@@H]2CC=CCCCC(=O)O)OCCO1
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCC1(CS[C@H]2C(O)CC(O)[C@@H]2CC=CCCCC(=O)O)OCCO1

Procedure:
0.1 g. 11-hydroxy-15,15-ethylenedioxy-9-oxo-13-thia-5-prostenoic acid is reduced with NaBH4 analogously to Example 14 and the 9,11-dihydroxy-15,15-ethylenedioxy-13-thia-5-prostenoic acid obtained subsequently stirred at room temperature for 2 hours with 10 ml. IN aqueous HCl and 10 ml. dioxan. The reaction mixture is saturated with NaCl extracted with benzene, the organic phase dried and the solvent distilled off to obtain, as the residue, 9,11-dihydroxy-15-oxo-13-thia-5-prostenoic acid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C1N2CN3CN(C2)CN1C3.[C:21]([O-])([O-])=[O:22].[Na+].[Na+]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:21]=[O:22])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cnc2[nH]ccc2n1
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1c[nH]c2ncc(Br)nc12
Temperature: 80 °C

Procedure:
To a reaction vial, 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1 g, 0.00505 mol) was added in TFA (10 ml). Hexamine (1.06 g, 0.00757 mol) was added and reaction mixture was heated to 80° C. in microwave for 15 min. After completion of the reaction, the reaction mixture was poured into aq. Na2CO3 solution. Solid obtained was filtered, dried and purified using column purification by eluting with 3-5% EtOAc in Hexanes to yield 0.450 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=O>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][C:20]3[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Reactant: Cn1ccnc1C=O
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(Cc3nccn3C)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 1 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 1-methyl-1H-imidazole-2-carbaldehyde (commercially available).
Reaction SMILES: [C:1]([C:4]1[C:11]([OH:12])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2].[I:14]N1C(=O)CCC1=O>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([C:8]#[N:9])=[C:10]([I:14])[C:11]=1[OH:12])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)c1cc(Cl)c(C#N)cc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C#N)c(I)c1O
Temperature: 80 °C
Yield: 65.9 %

Procedure:
The 4-acetyl-2-chloro-5-hydroxybenzonitrile (4.9 g, 25 mmol) was dissolved in acetic acid (61.2 mL), and the N-iodosuccinimide (6.8 g, 30 mmol) was added. The reaction was heated to 80° C. and, after heating for 18 hrs, the reaction was concentrated in vacuo to remove the acetic acid. The residue was taken up in ethyl acetate, washed with sodium bicarbonate water, brine, dried over magnesium sulfate and concentrated to give a dark oil. The crude product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-6-chloro-3-hydroxy-2-iodobenzonitrile as a yellow solid (5.3 g, 66%).
Reaction SMILES: [Na+:1].[Na+].[OH:3][C:4]1[CH:13]=[C:12]([S:14]([O-:17])(=[O:16])=[O:15])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:22][C:23]([C:25]1[C:26]([CH3:34])=[CH:27][C:28]([N+:31]([O-])=O)=[CH:29][CH:30]=1)=[O:24])=[CH:7][CH:8]=[C:9]2[S:18]([O-:21])(=[O:20])=[O:19]>[Pd].CN(C)C=O>[Na+:1].[Na+:1].[NH2:31][C:28]1[CH:27]=[C:26]([CH3:34])[C:25]([C:23]([NH:22][C:6]2[C:5]3[C:10](=[CH:11][C:12]([S:14]([O-:17])(=[O:16])=[O:15])=[CH:13][C:4]=3[OH:3])[C:9]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:8][CH:7]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccc(S(=O)(=O)[O-])c2cc(S(=O)(=O)[O-])cc(O)c12
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N)ccc1C(=O)Nc1ccc(S(=O)(=O)[O-])c2cc(S(=O)(=O)[O-])cc(O)c12

Procedure:
An 11.0 g portion of the above nitro derivative is hydrogenated in a Parr apparatus with 1.25 g of 10% palladium on carbon and 110 ml of dimethylformamide. The reaction mixture is filtered, concentrated to a small volume and ethanol is added to a total volume of 500 ml. The mixture is concentrated to 100 ml and ether is added. The solid is collected, washed with ether and dried giving 7.8 g of 4-(5-amino-o-toluamido)-5-hydroxy-1,7-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C@:23]1([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]1)[CH:17]=[CH:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:13]2[C:14]([C:30]([F:32])([F:33])[F:31])=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26][C:25](=[O:28])[NH:24]2)[CH:17]=[CH:16]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(O)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1

Procedure:
The mixture of cis-4-tert-butylcyclohexanol (30.4 mg, 0.000195 mol), (R)-4-(6-hydroxy-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (50.5 mg, 0.000162 mol) and triphenylphosphine (51.1 mg, 0.000195 mol) in tetrahydrofuran (2 mL, 0.02 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0383 mL, 0.000195 mol) was is added dropwise and was stirred and refluxed for 3 hours. The mixture was taken up into methylene chloride and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (22.2 mg, 30%). LCMS: Rf=2.41 min (450.46, M+1, 70%; 491.47, M+ACN, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ=8.25 (dd, J=8.7, 1.4 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.52 (dd, J=9.3, 2.3 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 5.98 (br. s., 1H), 4.45 (d, J=8.6 Hz, 1H), 4.41 (d, J=8.6 Hz, 1H), 4.38-4.26 (m, 1H), 2.19 (d, J=13.1 Hz, 2H), 1.89 (d, J=10.0 Hz, 2H), 1.87 (s, 3H), 1.59-1.48 (m, 2H), 1.21-1.05 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[S:12][C:5]2[NH:6][C:7]([C:9](Cl)=[O:10])=[CH:8][C:4]=2[CH:3]=1.[CH2:13]([O:15][C:16](=[O:30])[C:17]([C:20]1[CH:21]=[N:22][C:23]([NH2:29])=[C:24]([O:26][CH2:27][CH3:28])[CH:25]=1)([OH:19])[CH3:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:30])[C:17]([C:20]1[CH:21]=[N:22][C:23]([NH:29][C:9]([C:7]2[NH:6][C:5]3[S:12][C:2]([Cl:1])=[CH:3][C:4]=3[CH:8]=2)=[O:10])=[C:24]([O:26][CH2:27][CH3:28])[CH:25]=1)([OH:19])[CH3:18])[CH3:14]
Reactant: O=C(Cl)c1cc2cc(Cl)sc2[nH]1
Reactant: CCOC(=O)C(C)(O)c1cnc(N)c(OCC)c1
Product: CCOC(=O)C(C)(O)c1cnc(NC(=O)c2cc3cc(Cl)sc3[nH]2)c(OCC)c1

Procedure:
The title compound was prepared from 2-chloro-6H-thieno[2,3-b]pyrrole-5-carbonyl chloride and 2-(6-amino-5-ethoxy-pyridin-3-yl)-2-hydroxy-propionic acid ethyl ester in a manner analogous to that described hereinabove in Example 2 using appropriate starting materials. LC/MS+=438.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:45][O:46][CH2:47][CH2:48][CH2:49][NH2:50]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([NH:50][CH2:49][CH2:48][CH2:47][O:46][CH3:45])[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (2.46 g) and diisopropylethylamine (1.38 ml) were dissolved in N,N-dimethylformamide (50 ml), 3-methoxypropan-1-amine (990 μl) was added and the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with hexane to ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object compound (2.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([CH3:23])[N:28]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1noc(CN)n1
Product: Cc1noc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAN 1018782-82-5) and 3-methyl-1,2,4-oxadiazole-5-methanamine (CAN 90928-92-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 425.0644 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[S:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[S:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1sc(Nc2cccc(Br)c2)nc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
A solution of 8.6 g (0.05 mol) of 3-bromoaniline in 100 ml of dimethylformamide is added dropwise to a solution of 12.0 g (0.06 mol) of 2,4-dichloro-5-nitrothiazole in 100 ml of dimethylformamide at 0° C. to 5° C. in the course of about 2 hours and the mixture is subsequently stirred at the same temperature for a further 4 hours. It is then stirred into 1,000 ml of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred in 80 ml of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 16.0 g (95.7% of theory) of 2-(3-bromophenylamino)-4-chloro-5-nitrothiazole of melting point 191° C. to 192° C. (decomposition) are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][NH:19]C)[C:12]=2[F:21])[CH:9]=1)[C:5]#[N:6].[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH2:32][CH3:33])[NH:26][C:27]=1[C:28]([OH:30])=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>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH2:32][CH3:33])[NH:26][C:27]=1[C:28]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]=1[F:21])=[O:30]
Reactant: CCCc1nc(Cl)c(C(=O)O)[nH]1
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 64.4 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-propyl-1H-imidazole-5-carboxamide was prepared in a similar manner as described herein from 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.062 g, 0.20 mmol), 4-chloro-2-propyl-1H-imidazole-5-carboxylic acid (0.038 g, 0.20 mmol), HATU (0.091 g, 0.24 mmol), DIPEA (0.042 mL, 0.24 mmol) and DMF (2 mL). Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.062 g, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.73 (br. s., 1H), 8.12 (br. s., 1H), 7.81-7.84 (m, 1H), 7.45-7.52 (m, 3H), 7.37 (t, 1H), 4.53 (d, 2H), 2.55 (t, 2H), 1.64 (sex, 2H), 0.87 (t, 3H). ES-LCMS: m/z 481.0, 483.0 (M+1).