Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[S:22][CH:21]=[CH:20][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH2:3][CH2:2]1.N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C>[Si:32]([O:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]3[S:22][CH:21]=[CH:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1)([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: Oc1cccc(-c2nc(N3CCOCC3)c3sccc3n2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2nc(N3CCOCC3)c3sccc3n2)c1
Temperature: 70 °C

Procedure:
3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol [synthesized according to Hayakawa et al., Bioorganic & Med. Chem. 14:6847-6858 (2006)] (540 mg, 1.72 mmol, 1.0 eq.) was dissolved in DMF (5 ml). To this imidazole (936 mg, 13.8 mmol, 8.0 eq.) and TBDMSCl (909 mg, 6.02 mmol, 3.5 eq.) were added and the mixture was heated at 70° C. for 3 h. DMF was evaporated under reduced pressure and purification by flash chromatography (hexane:ethyl acetate, gradient from 100%-50% hexane in EtOAc) yielded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[F:35][C:36]1[CH:37]=[C:38]([C:42](=[O:49])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:39]=[CH:40][CH:41]=1.[H-].[Na+].FC(F)(OC1C=C(CBr)C=CC=1)C(F)F>C(OCC)(=O)C.COCCOC.O>[F:35][C:36]1[CH:37]=[C:38]([C:42](=[O:49])[CH:43]([CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:2]([F:14])([F:1])[CH:3]([F:4])[F:5])[CH:8]=2)[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: O=C1CCC(=O)N1Br
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (8.91 g, 42.8 mmol) in ethyl acetate (100 ml) were added N-bromosuccinimide (8.35 g, 46.9 mmol) and 2,2′-azobis(isobutyronitrile) (335 mg, 2.04 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solution was concentrated and the crystals were filtered with hexane. The filtrate was concentrated to prepare 3-(1,1,2,2-tetrafluoroethoxy)-a-bromotoluene. To a solution of ethyl 3-(3-fluorophenyl)-3-oxopropanoate (8.57 g, 40.8 mmol) in 1,2-dimethoxyethane (80 ml) was added sodium hydride (60% in oil, 1.63 g, 40.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (10 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate), and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-6:1) and recrystallized from ethyl acetate-hexane to give the objective substance (8.86 g, 52%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][N:24]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(Cl)Cl>[C:29]([C:28]1[C:23]([NH2:15])=[N:24][CH:25]=[C:26]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH:40]([CH3:41])[CH3:42])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[N:27]=1)#[CH:30]
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
TFA (34.45 g, 23.28 mL, 302.1 mmol) was added to a stirred solution of tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate (5 g, 9.968 mmol) in DCM (200 mL) and the reaction mixture stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo and the residue re-dissolved in DCM and stirred with saturated aqueous NaHCO3 for 30 minutes. The layers were separated and the organic layer washed with saturated aqueous NaHCO3 (×3). The combined aqueous layers were extracted with DCM (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from DCM and precipitate isolated by filtration and dried under vacuum to give the title product as a beige solid (2.8 g, 93% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.44 (t, 1H), 4.76 (s, 1H), 7.01 (s, 2H), 7.89 (d, 2H), 8.20 (d, 2H) and 8.75 (s, 1H) ppm; MS (ES+) 302.12.
Reaction SMILES: COC(N[C@@H](C(C)C)C(N1CC(=O)C[C@H]1C(OCC1C=CC=CC=1)=O)=O)=O.Cl.Cl.Cl.Cl.[CH2:32]([N:34]([CH2:80][CH3:81])[C@H:35]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[C:36]([N:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43]1[NH:44][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:63]=[CH:62][C:61]4[C:56](=[CH:57][CH:58]=[C:59]([C:64]5[NH:68][C:67]([C@@H:69]6[CH2:73][CH2:72][CH2:71][NH:70]6)=[N:66][CH:65]=5)[CH:60]=4)[CH:55]=3)=[CH:50][CH:49]=2)=[CH:46][N:47]=1)=[O:37])[CH3:33].[CH3:82][O:83][C:84]([NH:86][C@@H:87]([CH:91]1[CH2:96][CH2:95][O:94][CH2:93][CH2:92]1)[C:88](O)=[O:89])=[O:85].Cl.O=C1CN[C@H](C(OCC2C=CC=CC=2)=O)C1.COC(N[C@@H](C(C)C)C(O)=O)=O>>[CH2:80]([N:34]([CH2:32][CH3:33])[C@H:35]([C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)[C:36]([N:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43]1[NH:44][C:45]([C:48]2[CH:49]=[CH:50][C:51]([C:54]3[CH:55]=[C:56]4[C:61](=[CH:62][CH:63]=3)[CH:60]=[C:59]([C:64]3[NH:68][C:67]([C@@H:69]5[CH2:73][CH2:72][CH2:71][N:70]5[C:88](=[O:89])[C@@H:87]([NH:86][C:84](=[O:85])[O:83][CH3:82])[CH:91]5[CH2:96][CH2:95][O:94][CH2:93][CH2:92]5)=[N:66][CH:65]=3)[CH:58]=[CH:57]4)=[CH:52][CH:53]=2)=[CH:46][N:47]=1)=[O:37])[CH3:81]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Agent: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: Cl
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate, except that (R)-2-(diethylamino)-2-phenyl-1-((S)-2-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethanone 4HCl salt and (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid were used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS (ESI) m/z 863.81 [M+H]+. (34 mg, 39%).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:6]2[S:10][C:9]([C:11]3[S:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][CH:7]=2)[S:4][CH:5]=1.ClS([N:20]=[C:21]=O)(=O)=O>C(Cl)Cl>[C:21]([C:14]1[S:15][C:11]([C:9]2[S:10][C:6]([C:3]3[S:4][CH:5]=[CH:1][CH:2]=3)=[CH:7][CH:8]=2)=[CH:12][CH:13]=1)#[N:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: c1csc(-c2ccc(-c3cccs3)s2)c1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reaction time: 2 h

Procedure:
To a solution of α-terthienyl(2.46 g, 0.010 m) in methylene chloride (20 ml), was added chlorosulfonyl isocyanate (1.75 ml) in methylene chloride (15 ml). A yellow solid separated almost at once. The reaction mixture was stirred for 2 h and left overnight. Dimethyl formamide (5.0 ml) was added to the ice-cold reaction mixture dropwise. Addition of water (40 ml) precipitated a yellow solid insoluble in methylene chloride. The latter was removed in vacuo and the yellowish green solid was collected in a Buchner funnel and washed with water. Yield: 2 g; m.p. 122°-125° C. Recrystallization from the minimum amount of boiling ethanol-benzene(1:1) afforded 1.6 g of product(58.6% crude yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][N:37]6C(=O)C7C(=CC=CC=7)C6=O)(=[O:34])=[O:33])[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].NN>C(Cl)Cl.CO>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][NH2:37])(=[O:34])=[O:33])[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCN6C(=O)c7ccccc7C6=O)CC5)cc4s3)CC2)nc1
Agent: NN
Solvent: ClCCl
Solvent: CO
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCN)CC5)cc4s3)CC2)nc1
Temperature: 40 °C
Yield: 76.7 %

Procedure:
To a suspension of 2-(2-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)ethyl)isoindoline-1,3-dione (0.184 g, 0.274 mmol) in DCM (9.1 mL) and MeOH (9.1 mL) was added hydrazine (0.21 ml, 6.58 mmol). The mixture was heated in 40° C. oil bath overnight. The reaction became homogenous. The solvent was removed under reduced pressure. The residue was triturated in MeOH (6 mL) to afford desired product as a white solid (114 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 2H), 7.64 (dd, J=6.8, 5.2 Hz, 2H), 7.40 (dd, J=8.5, 1.8 Hz, 1H), 6.08 (s, 1H), 5.49-5.37 (m, 1H), 4.28-4.11 (m, 2H), 4.05 (d, J=2.8 Hz, 2H), 3.77-3.65 (m, 2H), 3.61 (t, J=5.7 Hz, 2H), 3.48-3.36 (m, 6H), 2.70 (s, 2H), 2.42 (t, J=7.5 Hz, 2H), 2.25-2.13 (m, 2H), 2.03-1.89 (m, 2H), 1.59 (dd, J=14.9, 7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:16][CH3:17])=[C:5]([C:11]([O:13]CC)=[O:12])[NH:6]2.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:16][CH3:17])=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2
Reactant: CCOC(=O)c1[nH]c2cccc(C)c2c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C(=O)O)[nH]c2cccc(C)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.5 %

Procedure:
A solution of 1.76 g of ethyl 4-methyl-3-methoxyindole-2-carboxylate in 90 ml of ethanol was treated with 45 ml of 2N sodium hydroxide solution and stirred at room temperature for 17 hours. The alcohol was evaporated and the residue was treated with 60 ml o of 2N hydrochloric acid. The separated crystals were filtered off, washed with water and dried. There were obtained 1.2 g (78%) of 4-methyl-3-methoxyindole-2-carboxylic acid as brown crystals with m.p. 136°.
Reaction SMILES: Br[CH2:2][C:3](=O)[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:5]([CH3:16])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[NH2:26][C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>C1COCC1.C([O-])(O)=O.[Na+]>[C:21]([O:20][C:18]([NH:17][C@H:4]([C:3]1[N:26]=[C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)=[CH:31][N:32]2[CH:2]=1)[C@@H:5]([CH3:16])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)CBr
Reactant: N#Cc1ccc(-c2ccc(N)nc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1cn2cc(-c3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of benzyl (2R,3S)-5-bromo-3-[(tert-butoxycarbonyl)amino]-2-methyl-4-oxopentanoate (Preparation 65, 400 mg, 0.966 mmol) in THF (15 mL) was added 4-(6-aminopyridin-3-yl)benzonitrile and the reaction stirred at room temperature for 3 days followed by 40° C. for 18 hours. The reaction was diluted with saturated aqueous NaHCO3 solution (80 mL), and extracted with EtOAc (3×50 mL). The organic layers were collected, dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with 0-60% MeCN in water followed by silica gel column chromatography eluting with 40% EtOAc in heptanes to afford the title compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C@@H:17]12[O:25][CH2:24][C@@H:22]([O:23]1)[CH:21]=[CH:20][C@@H:18]2[OH:19]>C(N(CC)CC)C>[C:1]1([NH:7][C:8]([O:19][C@H:18]2[CH:20]=[CH:21][C@H:22]3[CH2:24][O:25][C@@H:17]2[O:23]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)O[C@H]1C=C[C@H]2CO[C@@H]1O2
Yield: 86.4 %

Procedure:
0.56 g of phenyl isocyanate was added at room temperature to 30 ml of a dry toluene solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose under an inert atmosphere of nitrogen gas. Further, 0.1 ml of triethylamine was added thereto, and the reaction mixture was refluxed under heating for two hours. Completion of the reaction was confirmed by thin layer chromatography, and then the solvent was immediately distilled off under reduced pressure to obtain a syrup crude product. This crude product was purified by silica gel chromatography (ethyl acetate: hexane=1:3) to obtain 0.5 g of the desired product (Compound No. 23). The NMR analytical data of this product are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]=[C:10]([NH:33][C:34](C3OC=CC=3)=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=C=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([OH:25])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]=[C:10]([NH:33][C:34]([NH:41][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)c3ccco3)cc(-c3cccc(Cl)c3)c2c1
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)Nc3ccccc3)cc(-c3cccc(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
A mixture of (±)-2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.000210 mol) (see Example B8) and isocyanato-benzene (0.000630 mol; 3 equiv) in THF (1 ml) was stirred for 5 hours at 60° C. Water (a few drops) was added. The solvent was evaporated. The residue was HPLC purified. The product fractions were collected and the solvent was evaporated, yielding 0.071 g (56.77%) of (±)-N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinolinyl]-N′-phenylurea, MS (ESI) m/z: 594 596 598.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[CH:9]2[C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[H][H].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.N.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[CH:9]2[C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH2:30])=[NH:29])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: N=C(NO)c1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: N=C(N)c1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
100 mg of 4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-N-hydroxybenzamidine (3) were dissolved in 100 ml of tetrahydrofuran and, with 2 ml of conc. ammonia, hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and 25° C. for 30 hours. After addition of magnesium sulfate, the reaction solution was filtered. The filtrate was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoro-acetic acid)=80/20→10/90). This gave the product of molecular weight 435.48 (C25H23F2N3O2); MS (ESI): 436.18 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.ClC1C=CC(C(=O)CC)=CC=1.[Cl-].[In+3].[Cl-].[Cl-].[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:38]2[C:37]3[C:41](=[C:33]([CH2:32][S:31][CH3:30])[CH:34]=[CH:35][CH:36]=3)[NH:40][CH:39]=2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCC(O)(CCO)c1ccc(Cl)cc1
Agent: CCC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CCO)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3.04 g (14.10 mmol) of 3-(4-chlorophenyl)pentane-1,3-diol (preparation in analogy to the synthesis of Example 88A and 89A starting from 1-(4-chloropenyl)propan-1-one and ethyl acetate) and 3.12 g (14.10 mmol) of indium(III) chloride were added to 2.50 g (14.10 mmol) of the compound from Example 8A in 60 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off through kieselguhr. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 2.13 g (40% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=1)=[CH:12][CH:11]=3)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=1)=[CH:12][CH:11]=3)=[O:4]
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccc(Oc3ccc([N+](=O)[O-])cn3)cc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc2c(cn1)[nH]c1ccc(Oc3ccc(N)cn3)cc12

Procedure:
A suspension of 3.65 g of 6-(5-nitro-2-pyridyloxy)-β-carboline-3-carboxylic acid methyl ester and 0.5 g of Pd-C (10%) in 100 ml of methanol is hydrogenated at room temperature and under normal pressure. After absorption of the stoichiometric amount of hydrogen, the mixture is filtered and concentrated. The residue is crystallized from methanol/diethyl ether, yielding 2.84 g (85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: COc1ccc(F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)cc1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20.0 g (0.13 mol) of 5-fluoro-2-methoxybenzaldehyde are dissolved in 205 ml of methanol. Under argon, 2.45 g (54.9 mol) of sodium borohydride are added in small portions. The solution is stirred at RT for 4 hours. The solution is concentrated and the residue is taken up in water and stirred for 30 min. The aqueous phase is extracted with ethyl acetate and the organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:3][CH2:2]1.[F:28]C1C=C(C2C(C(C3C=C(C(=O)C(Cl)(Cl)Cl)NC=3)=O)=C(C)ON=2)C=CC=1F.C1(CN)CC1>>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[C:25]([F:28])[CH:26]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Agent: NCC1CC1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 19) and cyclopropylmethylamine (commercially available) in 35.8 yield. (m/e): 386.1 (MH+; 100%).
Reaction SMILES: [CH:1]([O-])([O-])OC.[C:6]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])(=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10].C1(C)C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:6]([NH:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[NH:16][C:17](=[O:22])/[CH:18]=[C:19](\[O:21][CH3:1])/[CH3:20])(=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC([O-])[O-]
Reactant: CCCCC(=O)Nc1cccc(NC(=O)CC(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 20 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
16.5 g of methyl orthoformate were added to a solution of 27.6 g of m-valeramido-acetylacetanilide in 50 ml of methanol and after the addition of 0.5 g of p-toluene sulfonic acid, the mixture was stirred for 72 hours at 20° C. 200 ml of toluene and 1 ml of quinoline were added and the mixture was heated at 140° C. for 1 hour while distilling a methanol-toluene azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8- 2 methylene chloride-acetone mixture yielded 20 g of m-valeramido-3-methoxy-crotonanilide melting at 115° C. and after crystallization from ethyl acetate melted at 116° C.
Reaction SMILES: O[CH2:2][CH:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:4]([CH3:6])[CH3:5].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.C(OCC)(=O)C>O1CCOCC1.CCCCCC.C(OCC)(=O)C.O>[N:32]([CH2:2][CH:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:4]([CH3:6])[CH3:5])=[N+:33]=[N-:34]
Reactant: CC(C)C(CO)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(C)C(CN=[N+]=[N-])NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 11.0 g (0.0464 mole) of benzyl N-[1-(hydroxymethyl)-2-methyl-propyl]carbamate in dioxane (100 mL) cooled to 0° C. was added diphenylphosphoryl azide 10.99 mL (1.1 eq) followed by the addition of DBU 8.32 mL (1.2 eq). The contents were allowed to warm to room temperature and stirred for 16 hrs. After the addition of ethyl acetate (300 mL) and water (100 mL), the organic layer was separated and then washed with satd. NaHCO3 (100 mL). The organic layer was then dried (magnesium sulfate) and then concentrated under vacuum. To this intermediate in DMSO (100 mL) was added sodium azide 7.54 g and the contents then heated to 90 degrees for 2 hrs. After addition of ethyl acetate and water the layers were separated. The organic layer was dried with magnesium sulfate followed by concentration under vacuum to afford an oil that was columned using hexane/ethyl acetate (0-70%) to afford benzyl N-[1-(azidomethyl)-2-methyl-propyl]carbamate 6.9 g as a colorless oil.