Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][F:16])[CH2:10][C:11](O)=[O:12])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].C(Cl)(=O)C(Cl)=O.C[N:28](C=O)C.N>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][F:16])[CH2:10][C:11]([NH2:28])=[O:12])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: N#Cc1ccc(N(CCF)CC(=O)O)cc1C(F)(F)F
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1ccc(N(CCF)CC(N)=O)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 303.3 %

Procedure:
A suspension of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2-fluoroethyl)glycine (0.031 g, 0.11 mmol) in anhydrous CH2Cl2 (2 mL), under nitrogen, was cooled in an ice bath and treated with oxalyl chloride (0.017 g, 0.13 mmol) and anhydrous DMF (˜0.001 g). The mixture was heated at 50° C. for 20 min. Upon cooling, the mixture was added into an aqueous solution of ammonia (30%, 10 mL) and stirred heavily for 5 min. The mixture was partitioned between CH2Cl2 (20 mL), water (20 mL) and methanol (5 mL). The aqueous phase was extracted 3 times with CH2Cl2/MeOH (˜10:1). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from CH2Cl2/MeOH to give 0.012 g (40% yield) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.8 Hz, 1H), 7.52 (bs, 1H), 7.21 (bs, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.8, 2.4 Hz, 1H), 4.61 (dt, J=47.4, 4.9 Hz, 2H), 4.08 (s, 2H), 3.82 (dt, J=26.0, 4.9 Hz, 2H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]2[C:14]3[CH2:15][CH2:16][CH:17]([CH2:19][OH:20])[CH2:18][C:13]=3[N:12]=[CH:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C3CC(CO)CCC=3N=C2)C=CC=CC=1.[O:63]([C:70]1[CH:77]=[CH:76][CH:75]=[CH:74][C:71]=1[CH2:72]Br)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[O:63]([C:70]1[CH:77]=[CH:76][CH:75]=[CH:74][C:71]=1[CH2:72][O:20][CH2:19][CH:17]1[CH2:16][CH2:15][C:14]2[N:10]([C:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:11]=[N:12][C:13]=2[CH2:18]1)[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: BrCc1ccccc1Oc1ccccc1
Reactant: OCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OCC1CCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C1
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(Oc2ccccc2COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 16 h

Procedure:
A 60% suspension of sodium hydride in mineral oil (4.1 g, 101 mmol) was added to a solution of a mixture of (1-(triphenylmethyl)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)-methanol and (3-(triphenylmethyl)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methanol (2.0 g, 5.1 mmol) in THF (8 ml). When the reaction had ceased tetrabutylammonium iodide (0.10 g, 0.25 mmol) and a solution of 2-phenoxybenzyl bromide (1.5 g, 5.6 mmol) in THF (5 ml) were added successively. The reaction mixture was stirred for 16 h. Water (100 ml) was added carefully. The mixture was extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (gradient from 50:50 to 100:0) as eluent, to give 1.21 g of 5-((2-phenoxybenzyloxy)methyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-((2-phenoxybenzyloxy)methyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole.
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11](C=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][CH:18](OC)[O:19][CH3:20].C[O-].[Na+]>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:8]1([S:7][C:1]2[CH:6]=[CH:5][C:4]([CH:18]([O:19][CH3:20])[O:17][CH3:16])=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:11][CH2:10][CH2:9]1
Reactant: O=Cc1ccc(SC2CCCCC2)cc1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(SC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.9 %

Procedure:
To a solution of 4-(cyclohexylthio)benzaldehyde (215 mg, 0.976 mmol) in methanol (4 mL) was added trimethylorthoformate (130 μL, 1.19 mmol) and p-toluenesulfonic acid (15 mg, 0.079 mmol), and the resulting solution stirred at room temperature for 72 hours. Sodium methoxide solution (25 wt %, 18 μL) was then added to the solution, and the volatiles removed in vacuo to afford crude cyclohexyl(4-(dimethoxymethyl)phenyl)sulfane (˜265 mg, quantitative yield) which was used directly without further purification.
Reaction SMILES: C=CCO[C@H](C1C2C(=CC=CC=2)N=CC=1)[C@H]1[N+]2(CC3C4C(=CC=CC=4)C=C4C=3C=CC=C4)C[C@H](C=C)[C@@H](CC2)C1.[Br-].[CH3:42][C:43]([CH3:67])=[CH:44][CH2:45][C:46]1[C:47]([OH:66])=[CH:48][C:49]([O:64][CH3:65])=[C:50]([C:53](/[CH:55]=[CH:56]/[C:57]2[CH:58]=[CH:59][C:60]([OH:63])=[CH:61][CH:62]=2)=[O:54])[C:51]=1[OH:52].[OH-].[Na+].OS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:42][C:43]([CH3:67])=[CH:44][CH2:45][C:46]1[C:47]([OH:66])=[CH:48][C:49]([O:64][CH3:65])=[C:50]2[C:53](=[O:54])[CH2:55][CH:56]([C:57]3[CH:58]=[CH:59][C:60]([OH:63])=[CH:61][CH:62]=3)[O:52][C:51]=12
Reactant: COc1cc(O)c(CC=C(C)C)c(O)c1C(=O)/C=C/c1ccc(O)cc1
Agent: C=CCO[C@H](c1ccnc2ccccc12)[C@@H]1C[C@@H]2CC[N+]1(Cc1c3ccccc3cc3ccccc13)C[C@@H]2C=C
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(O)c(CC=C(C)C)c2c1C(=O)CC(c1ccc(O)cc1)O2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the suspension of the O'Donnell phase transfer catalyst O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (34 mg, 0.056 mmol) in 1 ml of toluene is added xanthohumol (2 OH groups protected) (in part TIPS-protected: 37 mg, 0.056 mmol) in 1 ml of toluene. Subsequently, 0.5 ml of 25% NaOH is added and the mixture is stirred for 24 h at room temperature. For workup, 20 ml of H2O and 20 ml of ethyl acetate are added. The aqueous phase is acidified with H2SO4 and extracted twice with ethyl acetate. The organic phase is washed with NH4Cl solution and H2O, dried and eluted through a silica gel column using CHCl3/methanol. Removal of protection proceeds in a manner known from the literature.
Reaction SMILES: BrP([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:36][C:37]1[CH:38]=[C:39](/[CH:44]=[CH:45]/[CH:46]=O)[CH:40]=[CH:41][C:42]=1[Cl:43]>C1COCC1>[Cl:43][C:42]1[CH:41]=[CH:40][C:39](/[CH:44]=[CH:45]/[CH:46]=[CH:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[CH:38][C:37]=1[Cl:36]
Reactant: O=C/C=C/c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CP(Br)(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C=C/C=C/c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.8 %

Procedure:
A mixture of 4-nitro-benzyl bromide (200.0 g, 0.93 mol) and triphenylphosphine (244.0 g, 0.93 mol) in CHCl3 (1.5 L) was heated to reflux for overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo to remove CHCl3 and then suspended in Et2O and stirred rigorously. The suspension was filtered, and the off-white solid was washed with Et2O, dried at 80° C. for 16 hours to give 433.0 g (0.91 mol, 98%) of bromo[(4-nitrophenyl)methyl]triphenylphosphine. A solution of bromo[(4-nitrophenyl)methyl]triphenylphosphine (100.0 g, 0.23 mol) in dry THF (500 mL) was cooled to 5° C. n-Butyl lithium (n-BuLi) (2.4 M, 96 mL, 0.23 mol) was added dropwise to maintain the temperature between 5° C. to 10° C. The cooling bath was then removed, and the reaction mixture was allowed to warm to room temperature. After 4 hours, a solution of (trans)-3-(3,4-dichlorophenyl)-2-propenal (36.2 g, 0.18 mol) in THF (100 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. Purification by flash chromatography (silica gel, 20% EtOAc/hexane) yielded 16.0 g (0.05 mol, 28%) of the desired product. mp 125-135° C.
Reaction SMILES: C[O-].[Na+:3].[F:4][C:5]([F:32])([F:31])[C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH2:14][N:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:26][C:27]([OH:29])=[O:28])=[N:16]3)=[N:11][C:10]=2[CH:30]=1>CO>[F:31][C:5]([F:4])([F:32])[C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH2:14][N:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:26][C:27]([O-:29])=[O:28])=[N:16]3)=[N:11][C:10]=2[CH:30]=1.[Na+:3]
Reactant: O=C(O)Cc1nn(Cc2nc3cc(C(F)(F)F)ccc3s2)c(=O)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])Cc1nn(Cc2nc3cc(C(F)(F)F)ccc3s2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium methoxide (54 mg) was added to 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (0.4 g) in methanol 10 ml) at room temperature. After the addition was complete, a clear solution was obtained which was stirred for 15 minutes at room temperature. The excess methanol was evaporated. The residue was triturated with ether (20 ml) and filtered to obtain the product (0.43 g; m.p. 300° C.).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH:20]=3)[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH:20]=3)[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnc(C)o4)c3)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnc(C)o4)c3)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.12 g, 0.29 mmol) (from Example 8 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.07 g, 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:6][CH:7]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:16]1([O:24][CH3:25])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:19]2[N:11]([C:9](=[O:10])[NH:8][C:4]3[CH:5]=[N:6][CH:7]=[CH:2][CH:3]=3)[CH2:12][CH2:13][C:14]=2[CH2:15]1
Reactant: OB(O)c1ccco1
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(Br)c1)CC2
Product: COC1(c2ccco2)CC2=C(C=C1C(F)(F)F)N(C(=O)Nc1cccnc1)CC2
Yield: 80 %

Procedure:
This was prepared from 1-(5-bromopyrid-3-ylcarbamoyl)-5-methoxy-6-trifluoromethylindoline and 2-furylboronic acid by the same method as for Example 10, affording the title compound as a pale brown crystalline solid in 80% yield, m.p. 92-94° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([O:14][CH3:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
4-(4-Chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.641 mmol) was added portionwise as a solid to a suspension of sodium hydride (0.018 g, 0.770 mmol) in dimethylformamide (6 mL) at room temperature. After 30 minutes, methyl iodide (0.109 g, 60 uL, 0.770 mmol) was added and the mixture was stirred overnight. The mixture was poured into an equal volume of water and extracted with ethyl acetate (2×10 mL). The ethyl acetate extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a tan oil. The crude oil was purified by silica gel chromatography (hexane to 60:40 hexane/ethyl acetate gradient) to afford 4-(4-Chloro-phenyl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (108 mg, 52%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH:15]C(=O)OC(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:25]1[S:33][C:28]2[C:29](=[O:32])[NH:30][CH2:31][C:27]=2[CH:26]=1>CCCCO.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:15][C:10]1[C:9]([C:25]2[S:33][C:28]3[C:29](=[O:32])[NH:30][CH2:31][C:27]=3[CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1NCc2cc(Br)sc21
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: [Na+]
Solvent: CCCCO
Product: Nc1ncccc1-c1cc2c(s1)C(=O)NC2
Temperature: 110 °C
Yield: 72 %

Procedure:
A solution of tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carba mate (736 mg, 2.3 mmol), 2-bromo-4H-thieno[2,3-c]pyrrol-6(5H)-one (500 mg, 2.3 mmol) and Pd(PPh3)4 (40 mg, 0.035 mmol) in n-BuOH (5 mL) and 2.0 M Na2CO3 (4.6 mL) was degassed and the resulting reaction mixture was refluxed at 110° C. for 2 h. Upon completion, the reaction was cooled to room temperature, filtered, and washed with MeOH (10 mL) and water (2×10 mL). The solid was dried under high vacuum yielding 2-(2-aminopyridin-3-yl)-4H-thieno[2,3-c]pyrrol-6(5H)-one (383 mg, 72% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (br. s., 1H), 8.00 (dd, J=5.0, 1.8 Hz, 1H), 7.52 (dd, J=7.3, 1.8 Hz, 1H), 7.36 (s, 1H), 6.66 (dd, J=7.4, 4.9 Hz, 1H), 5.99 (s, 2H), 4.32 (s, 2H); MS (EI) m/z=232.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=[C:11]([CH2:14][OH:15])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([CH:14]=[O:15])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCC1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=CC1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
Manganese dioxide (17.7 g, 203 mmol) was added to a solution of [5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-methanol (7.98 g, 25.4 mmol) in chloroform (170 ml). After stirring for 4 h at 60° C. the reaction mixture was cooled to 20° C. and filtered. The filtrate was concentrated and the residue was purified by chromatography over silica (cyclohexane/ethylacetate; 3/1) to give 4.1 g of a yellow oil. 1H-NMR (CDCl3, 400 MHz): 9.93 (s, 1H) 7.42-7.48 (m, 3H), 3.88 (d, 2H), 3.50 (d, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[C:8]([NH:10][C@H:11]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([O:36]C)=[O:35])=[O:27])[CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:9])(=O)C.CO.[OH-].[Na+].Cl>C1COCC1>[CH2:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][C@@H:11]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([OH:36])=[O:35])=[O:27])[NH:10][C:8](=[O:9])[C:7]1[CH:38]=[CH:39][CH:40]=[C:5]([OH:4])[CH:6]=1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cccc(OC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCC[C@H](NC(=O)c1cccc(O)c1)C(=O)N[C@H]1CCC[C@H]1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To a mixture of methyl (1R,2S)-2-({N2-(3-acetoxybenzoyl)-N5-[(benzyloxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.35 g), methanol (3.0 ml), and THF (3.0 ml) was added a 1 M aqueous sodium hydroxide solution (1.9 ml) under ice-cooling, followed by stirring at room temperature over one night. Further, to the reaction mixture were added a 1 M aqueous sodium hydroxide solution (1.0 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. After completion of the reaction, 1 M hydrochloric acid was added thereto under ice-cooling, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and diisopropyl ether and ethyl acetate were added to the purified product obtained to give a solid. The solid was collected by filtration to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-(3-hydroxybenzoyl)-L-ornithyl}amino)cyclopentanecarboxylic acid (0.12 g).
Reaction SMILES: [CH3:1][O:2][P:3]([CH3:7])(=[O:6])[O:4][CH3:5].[Li]CCCC.C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1>C1COCC1>[CH3:1][O:2][P:3]([CH2:7][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:14])(=[O:6])[O:4][CH3:5]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cccc(Cc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1cccc(Cc2ccccc2)c1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a −78° C. THF solution(10 mL) of dimethylmethylphosphonate (0.423 mL, 3.9 mmol) was added 1.6M BuLi in hexanes (2.44 mL, 3.9 mmol). After 1 h a THF solution (5 mL) of 3-benzyl-benzoic acid methyl ester (589 mg, 2.6 mmol) was added. After 15 min. the reaction mixture was warmed to room temperature and stirred an additional 3 h. The reaction mixture was quenched with an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The residue was subjected to column chromatography (18 ethyl acetate: 1 hexanes) to provide [2-(3-benzyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (677 mg, 2.12 mmol) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([C:11]([O:13]C)=[O:12])[CH2:8][CH2:7][C:5]=2[N:6]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: COC(=O)C1CCc2nc(N)sc2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2c(s1)CC(C(=O)O)CC2

Procedure:
A solution of (±)-methyl 2-amino-4,5,6,7-tetrahydro-6-benzothiazolecarboxylate (8.5 g) (Example D) in 200 ml of 2N sulfuric acid is refluxed for eight hours. The solution is cooled in ice and adjusted to pH 6 with concentrated sodium hydroxide solution. The title compound precipitates as a beige solid; mp 220°-250° C. (dec).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C@@H:15]1[C@@H:22]2[C@@H:18]([O:19][C:20](=[O:23])[CH2:21]2)[CH2:17][C@H:16]1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.[OH-].[Na+]>C1COCC1.ClCCl>[OH:23][CH2:20][CH2:21][C@@H:22]1[C@@H:15]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@H:16]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:17][C@@H:18]1[OH:19]
Reactant: CCCCCCCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCC[C@@H]1[C@@H](CCO)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A solution of LiAlH4 (1.5 mL, 1.5 mmol, 1 M/THF) was added to a 0° C. solution of 5-4 (453 mg, 1.34 mmol) in THF (5 mL). After 3 h, H2O (5 mL) was added dropwise followed by dichloromethane and 15% NaOH (10 mL). The reaction was allowed to warm to room temperature and was stirred further for 30 min. The resulting mixture was extracted with dichloromethane (3×) and the combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (Isco Combiflash unit) gave the title compound (447 mg, 97%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:14]O)[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=NO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a 25° C. solution of 1-benzyl-3-methyl-piperidin-4-one oxime in anhydrous THF (20 mL) was added LAH (1.0 M solution TBF), (15 mL, 15 mmol). After being stirred at 50° C. overnight, the resultant mixture was quenched with 20% KOH solution. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude mixture ((±)-cis: (±)-trans=1:1) 1-benzyl-3-methyl-piperidin-4-ylamine (1). LC/MS m/z: 205 (M+H)+. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][CH2:17][C:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][CH2:17][C:18]3([CH2:21][OH:22])[CH2:20][CH2:19]3)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NCC1(CO)CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnn2cc(Br)cc2c1NCC1(CO)CC1
Yield: 73.7 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 45 mg, 0.164 mmol), (1-(aminomethyl)cyclopropyl)methanol HCl salt (25.9 mg, 0.189 mmol) and DIPEA (0.072 mL, 0.410 mmol) in NMP (0.5 mL) was heated to 110° C. for 1 hr. The reaction mixture was purified on preparative HPLC to afford the title compound (41 mg, 74%). HPLC (condition G): retention time=2.73 min. LCMS (condition B): m/z 339.1, 341.1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][N:12]=1.N1C=CC=CC=1>O>[N+:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1n[nH]c2ccc([N+](=O)[O-])cc12)c1ccccc1
Reaction time: 18 h

Procedure:
N-(5-Nitro-1H-indazol-3-yl)benzamide can be obtained in the following way: 0.39 ml of benzoyl chloride is added dropwise to a solution, cooled to 0° C., of 0.6 g of 3-amino-5-nitro-1H-indazole and of 5 ml of pyridine. The medium is brought back to a temperature in the region of 20° C. and maintained with stirring for 18 hours. After addition of 20 ml of distilled water, the medium is extracted with 20 ml and 10 ml of ethyl acetate. The organic phases are pooled, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane/methanol (99/1 by volume) mixture as eluent. 0.9 g of N-(5-nitro-1H-indazol-3-yl)benzamide is thus obtained in the form of an orange solid melting at 231° C.