Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:17]([Cl:18])=[CH:16][S:15][CH:14]=1)=S.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(OCC)(=O)C>C1COCC1.O>[Cl:18][C:17]1[C:13]([NH:12][C:10]2[NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[N:1]=2)=[CH:14][S:15][CH:16]=1
Reactant: Nc1cc(F)ccc1NC(=S)Nc1cscc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2[nH]c(Nc3cscc3Cl)nc2c1
Yield: 24.3 %

Procedure:
1-(2-Amino-4-fluoro-phenyl)-3-(4-chloro-thiophen-3-yl)-thiourea (625 mg) was dissolved in THF and a solution of NaOH (0,207 g) in water (9 ml) was added. Within 5 min a solution of p-toluenesulfonyl chloride (0,395 g) in THF (10 ml) was added dropwise. After stirring for one hour at room temperature water and ethyl acetate were added to the reaction mixture. The organic layer was separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4), treated with charcoal, filtered and the solvent evaporated to yield the desired product (135 mg).
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[CH:3][N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: CCC(COC)n1cc(I)c2c(OC)nccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(COC)n1cc(-c2ccc(S(N)(=O)=O)cc2)c2c(OC)nccc21
Temperature: 130 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine (70.8 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (60.0 mg), tetrakis(triphenylphosphine)palladium(0) (19.2 mg) and potassium carbonate (46.0 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (24.2 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[N:4]=[CH:3]1.[NH2:10][C:11]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[N:29][N:28]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:25]3=[N:26][CH:27]=2)=[CH:18][C:12]=1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].N1C=CC=CC=1.ClCCl.C(O)C(N)(CO)CO>ClCCl>[CH3:17][N:15]([CH3:16])[C:13]([C:12]1[CH:18]=[C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[N:29][N:28]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:25]3=[N:26][CH:27]=2)[CH:20]=[CH:21][C:11]=1[NH:10][C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:8])=[O:14]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Reactant: Cn1cnc(C(=O)Cl)c1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Reaction time: 16 h
Yield: 51.7 %

Procedure:
1-Methyl-1H-imidazole-4-carbonyl chloride (0.579 mmol) was suspended in dichloromethane (4 mL) and a solution of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (150 mg, 0.289 mmol) in 20% v/v pyridine/dichloromethane (1.0 mL) was added. After 16 h, PS-trisamine (Argonaut Technologies, Inc.) was added (3.0 eq. relative to acid chloride) and the suspension was filtered 3 hours later and the resin was rinsed with dichloromethane. After concentration of the filtrates in vacuo, the resulting residue was purified by silica gel chromatography to afford 1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (93.5 mg, 50.5%). MS: m/z 640 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19](OCC)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1.[BH4-].[Na+].O>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([CH2:19][OH:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1
Reactant: CCOC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Yield: 95.5 %

Procedure:
To a solution of ethyl 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (3 g, 8.73 mmol) and NaBH4 (1.58 g, 43.67 mmol) in CH3OH/DCM (30 mL/10 mL) was stirred at room temperature for 2 hours. The mixture was poured to H2O and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum to give (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl) methanol (2.54 g, yield: 95.5%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:13][CH3:14])(=[O:12])[C:10]#[CH:11].C(=O)([O-])[O-].[K+].[K+].C1COCC1>O.[Cu]I>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[C:10][C:9]([O:13][CH3:14])=[O:12])=[N:3][CH:4]=1
Reactant: C#CC(=O)OC
Reactant: Nc1cnc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C#Cc1cnc(N)cn1
Temperature: 65 °C
Yield: 38 %

Procedure:
To a 5 mL of microwave vial was added 5-iodopyrazin-2-amine (100 mg, 0.452 mmol), methyl propiolate (161 μL, 1.810 mmol), potassium carbonate (125 mg, 0.905 mmol), copper (I) iodide (3.45 mg, 0.018 mmol), and THF (1508 μL). The reaction mixture was heated at 65° C. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (20% EtOAc in DCM) yielding methyl 3-(5-aminopyrazin-2-yl)propiolate (38%). LCMS (m/z): 178.4 (MH+), 0.48 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([CH3:22])[C@@H:17]2[CH:23]=O)=[O:15])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][CH2:23][C@H:17]2[C@@H:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:15])=[N:30][CH:31]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2C=O)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac-cis-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidine-2-carbaldehyde and 5-fluoropyridin-2-amine in methanol/acetic acid (50:1) was added sodium cyanoborohydride at 0° C. The reaction was then stirred at rt overnight. After ˜16 h, the reaction mixture was transferred to a seperatory funnel, diluted with EtOAc, saturated NaHCO3 and the layers separated. The organic layer was washed with water, brine, dried (MgSO4), and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 443.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:9]2[CH2:10][C@@H:11]3[C:21]([C:22](=[O:23])[C:8]=2[C:7]([OH:33])=[CH:6][CH:5]=1)=[C:20]([OH:24])[C@@:19]1([OH:25])[C@H:13]([C@H:14]([N:30]([CH3:32])[CH3:31])[C:15]([OH:29])=[C:16]([C:26]([NH2:28])=[O:27])[C:17]1=[O:18])[CH2:12]3)[CH3:3].C1C=CC=CC=1.[CH3:40][OH:41].C([OH:44])C.C[C:46]([N:48](C)C)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:3][N:2]([C:4]1[C:9]2[CH2:10][C@@H:11]3[C:21]([C:22](=[O:23])[C:8]=2[C:7]([OH:33])=[CH:6][CH:5]=1)=[C:20]([OH:24])[C@@:19]1([OH:25])[C@H:13]([C@H:14]([N:30]([CH3:32])[CH3:31])[C:15]([OH:29])=[C:16]([C:26]([NH2:28])=[O:27])[C:17]1=[O:18])[CH2:12]3)[CH3:1].[CH2:46]([NH:48][C:16]([CH2:15][OH:29])([CH2:17][OH:18])[CH2:26][OH:27])[C:40]([OH:44])=[O:41]
Reactant: CCO
Reactant: CC(=O)N(C)C
Reactant: CO
Agent: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CNC(CO)(CO)CO

Procedure:
Tri-tetracycline complexes of the invention can be identified by chromatography. Minocycline was subjected to thin layer chromatography on a Kieselgel G thin layer plate in a 50:10:10:10:10:10 solvent mixture containing benzene, methanol, ethanol, ethyl acetate, dimethylformamide and dimethylacetamide. Rf of minocycline:0.16, whereas the Rf value of the complex of minocycline formed with N-tris(hydroxymethyl)methylglycine is 0.63. Chelocardin was identified in a similar way, its Rf value in the previous system is 0.21, whereas the Rf value of the complex of chelocardin formed with N-tris(hydroxymethyl)methylglycine is 0.42. The Rf value of minocycline hydrochloride on Kieselgel G thin layer plate in a 60:20:10:10 solvent system of benzene methanol, ethyl acetate and dimethylformamide is 0.1, whereas the Rf value of the complex of minocycline with tris(hydroxymethyl)aminomethane is 0.2.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[CH2:9]([CH:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[OH:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].N1C=CC=CC=1.[CH3:53][NH:54][CH2:55][CH2:56][CH2:57][OH:58]>CCOCC>[OH:58][CH2:57][CH2:56][CH2:55][N:54]([CH3:53])[C:5](=[O:4])[O:28][CH:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNCCCO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCO
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A solution of trichloromethyl chloroformate (340 μL, 2.8 mmol) in anhydrous Et2O (5 mL) was cooled (−15° C.) and treated with a solution of dilinoleyl methanol (1.0 g, 1.9 mmol) and pyridine (230 μL, 2.8 mmol) in Et2O (5 mL). After stirring (1 h) the reaction mixture was filtered through a frit and the filtrate was added, dropwise, to a cool (0° C.) solution of 3-methylamino-propan-1-ol (1.1 mL, 11.3 mmol) in Et2O (5 mL). After stirring (5 min) the reaction mixture was filtered and concentrated. The crude material was subjected to chromatography (12%→20% EtOAc-hexanes) to yield (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (3-hydroxypropyl)(methyl)carbamate (960 mg, 79%) as a colorless oil. Rf 0.17 (10% EtOAc-hexanes), FW 644.07, C42H77NO3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH:23][C:33]([C:30]3[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][N:31]=3)=[O:34])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)F)COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=NC(c2cc(NC(=O)c3ccc(Br)cn3)ccc2F)(C(F)F)COC1
Reaction time: 8 h

Procedure:
To a solution of 325 mg (0.952 mmol) [5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester, 212 mg (1.047 mmol) 5-bromo-pyridine-2-carboxylic acid, 168 mg (1.238 mmol) HOAt and 0.34 ml (2.38 mmol) Et3N in 5 ml DCM were added 237 mg (1.24 mmol) EDC.HCl. The mixture was stirred overnight. The mixture was diluted with EtOAc and washed with water, 1N HCl, brine and 5% aqueous NaHCO3. The organic phase was dried with MgSO4.H2O, filtered and purified by chromatography on silica gel (hexane/14-18% EtOAc) to give the desired product as colorless foam.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:38]([S:42](Cl)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41].O>C(Cl)Cl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:42]([CH2:38][CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Oc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc(C(=O)NN3CCCCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide, Ex. 2, Step 1 (320 mg, 0.72 mmol) in 10 ml CH2Cl2 was cooled to 0° C. Triethylamine (100 μl, 0.72 mmol) was added followed by 1-butanesulfonyl chloride (93 μl, 0.72 mmol) and the reaction mixture was stirred at room temperature overnight. Water was added and the mixture extracted with CH2Cl2 (3×20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2) afforded 230 mg (57%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(O)[CH3:17])[CH2:15][CH2:14]1.ClC1C=CC(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2CC2)C)=CC=1>>[CH:13]1([C:16]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=2)[CH3:17])[CH2:15][CH2:14]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(C(F)(F)F)cc1)C1CC1
Agent: CSCc1cccc2c(C(C)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(C(F)(F)F)cc3)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 462 mg (2.61 mmol) of the compound from Example 8A and 600 mg (2.61 mmol) of the compound from Example 139A in analogy to the synthesis of the compound from Example 184. 273 mg (27% of theory) of the target compound were obtained.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[CH2:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)[CH3:27]>>[CH2:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9])[CH3:27]
Reactant: CC[C@@H]1CCCN1
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO
Product: CC[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and 2-(R)-ethyl-pyrrolidine (CAS 460748-80-5) MS (M+H) 431.3.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:2][C:3]1[CH:4]=[C:5]([N:10]2[C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[NH:11]2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(NN)cc1C
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1

Procedure:
A solution of 3,4-dimethylphenylhydrazine hydrochloride (17.7 g; 0.1 mol.), ethyl acetoacetate (13.0 g; 0.1 mol.) and sodium acetate (8.2 g; 0.1 mol.) in glacial acetic acid (250 mL) was stirred and heated under reflux for 24 h.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH2:32][F:33])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[F:33][CH2:32][CH2:31][CH2:30][O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:25])[CH3:24])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCCCF)c2o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=CC(=O)O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCCCF)c2o1
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-{7-[2-(3-fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-{7-[2-(3-Fluoropropoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid was isolated as a white solid. 1H-NMR (CDCl3),: 7.58 (d, J=6.7 Hz, 1H, Ar—H), 7.56 (d, J=6.2 Hz, 1H, Ar—H), 7.29 (t, J=7.6 Hz, 1H, Ar—H), 7.28 (d, J=2.2 Hz, 1H, Ar—H), 7.17 (d, J=2.1 Hz, 1H, Ar—H), 7.11 (s, 1H, furan-H), 6.59 (s, 1H, C═C—H), 4.25 (dt, J=47.1 Hz, J=6.1 Hz, 2H, O—CH2—CH2—CH2F), 3.46 (t, J=5.9 Hz, 2H, O—CH2—CH2—CH2F), 3.38 (m, 1H, CH3—CH—CH3), 2.95 (m, 1H, CH3—CH—CH3), 2.56 (s, 3H, C═C—CH3), 1.70 (m, 2H, O—CH2—CH2—CH2F), 1.32 (d, J=5.7 Hz, 6H, CH3—CH—CH3), 1.30 (d, J=6.6 Hz, 6H, CH3—CH—CH3).
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]=1[C:14]([O:16]C)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=[N:21][CH:20]=1>>[CH3:13][CH:10]1[CH2:11][CH2:12][C:6]2[C:5]3[C:14](=[O:16])[N:27]([CH2:26][CH2:25][CH2:24][N:23]4[C:19]([CH3:18])=[CH:20][N:21]=[CH:22]4)[C:2](=[S:3])[NH:1][C:4]=3[S:8][C:7]=2[CH2:9]1
Reactant: Cc1cncn1CCCN
Reactant: COC(=O)c1c(N=C=S)sc2c1CCC(C)C2
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc3c(c2c1=O)CCC(C)C3

Procedure:
The compound was synthesized starting from methyl 4,5,6,7-tetrahydro-2-isothiocyanato-6-methylbenzo[b]thiophene-3-carboxylate (0.10 g, 0.37 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.052 g, 0.37 mmol) as described above.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[CH:20][C:15]3[N:16]=[C:17]([NH2:19])[O:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH2:22]1[O:31][C:30]2[C:25](=[C:26]([C:32](O)=[O:33])[CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[CH:20][C:15]3[N:16]=[C:17]([NH:19][C:32]([C:26]4[C:25]5[O:24][CH2:23][CH2:22][O:31][C:30]=5[CH:29]=[CH:28][CH:27]=4)=[O:33])[O:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N)oc3c2)ccn1
Reactant: O=C(O)c1cccc2c1OCCO2
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
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc3nc(NC(=O)c4cccc5c4OCCO5)oc3c2)ccn1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
4-(2-Amino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (1 eq) and 2,3-dihydro-1,4-benzodioxane-5-carboxylic acid (1 eq) were dissolved in DMF. To this solution were added DIPEA (3 eq) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (1 eq). The mixture was stirred at 40° C. overnight, then diluted with ethyl acetate and washed once each with 1N HCl, saturated aqueous sodium bicarbonate, and brine, and finally dried with anhydrous sodium sulfate, filtered, and concentrated. This was purified by preparatory reverse phase HPLC. MH+=447.0.
Reaction SMILES: CO.Cl.C(OCC)(=O)C.[CH2:10]([O:17][C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=[O:28])[CH2:23][C@H:22]1[O:34][CH3:35])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:36][CH2:37]C(Cl)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:36][CH2:37][C:27]([N:24]1[CH2:25][CH2:26][C@H:21]([NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:22]([O:34][CH3:35])[CH2:23]1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CO[C@@H]1CN(C(=O)CCl)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (10 ml), ethyl acetate (10 ml) and a 4 N hydrochloric acid/ethyl acetate solution (30 mL) were added to tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (40a) (1.88 g, 5.16 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, azeotropically dehydrated by adding toluene, and dissolved in methylene chloride (100 ml), followed by adding diisopropylethylamine (2.1 g). Chloroacetyl chloride (640 mg, 5.68 mmol) was dissolved in methylene chloride (50 ml), and the solution was added dropwise at 0° C. Following the dropwise addition, the mixture was stirred at 0° C. to room temperature overnight. The reaction solution was washed with water and aqueous sodium bicarbonate, concentrated under reduced pressure, and then azeotropically dehydrated by adding toluene to obtain the title compound. Half of the resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[C:7]([N+]([O-])=O)=[CH:8][C:9]([CH3:13])=[N+:10]([O-:12])[CH:11]=1.S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:7]1[C:6]([O:5][CH3:4])=[CH:11][N+:10]([O-:12])=[C:9]([CH3:13])[CH:8]=1
Reactant: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)[n+]([O-])cc1OC
Temperature: 20 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
20 ml of a 30% strength sodium methylate solution are added dropwise to a suspension of 16.9 g of 5-methoxy-2-methyl-4-nitropyridine 1-oxide in 170 ml of dry methanol and the mixture is stirred at 20° C. for 15 hours and then at 50° C. for 4 hours. The pH is brought to 7 by careful addition of concentrated sulphuric acid, while cooling with ice, the mixture is concentrated, the residue is extracted by stirring with 200 ml of methylene chloride, the insoluble constituents are filtered off, 10 ml of toluene are added and the mixture is concentrated to dryness again. 15.2 g (98% of theory) of 4,5-dimethoxy-2-methylpyridine 1-oxide are obtained as colourless crystals of m.p. 118°-121° C.