Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:15][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][C@@H:11]3[CH2:13]2)[CH:17]=[N:18][CH:19]=1)=[O:23]
Reactant: NCCc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NCCc4ccccc4F)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 2-(2-fluorophenyl)ethanamine were processed as described in Example 33C to provide the title compound. MS (ESI) m/z 455 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](B1OC(C)(C)C(C)(C)O1)=[CH:8]2.Cl[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:23]1[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=1)=[CH:8]2
Reactant: COc1cccc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1cccc2cc(-c3cnnc(Cn4ccnc4C)c3)ccc12

Procedure:
The title compound, MS: m/e 331.4 (M+H+), was prepared from 2-(5-methoxy-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: C(OC(N1CCC(C2C=CC(OCCCOCC3C=CC=CC=3OC)=CC=2)C(O)C1)=O)(C)(C)C.ClCC1C=CC2C(=CC(OCOCC[Si](C)(C)C)=CC=2)C=1.C(OC(N1CCC(C2C=CC=CC=2OCCCOCC2C=CC=CC=2OC)C(OCC2C=CC3C(=CC(OCOCC[Si](C)(C)C)=CC=3)C=2)C1)=O)(C)(C)C.[C:110]([O:114][C:115]([N:117]1[CH2:122][CH2:121][CH:120]([C:123]2[CH:128]=[CH:127][C:126]([O:129][CH2:130][CH2:131][CH2:132][O:133][CH2:134][C:135]3[CH:140]=[CH:139][CH:138]=[CH:137][C:136]=3[O:141][CH3:142])=[CH:125][CH:124]=2)[CH:119]([O:143][CH2:144][C:145]2[CH:154]=[CH:153][C:152]3[C:147](=[CH:148][C:149]([O:155]COCC[Si](C)(C)C)=[CH:150][CH:151]=3)[CH:146]=2)[CH2:118]1)=[O:116])([CH3:113])([CH3:112])[CH3:111]>>[C:110]([O:114][C:115]([N:117]1[CH2:122][CH2:121][CH:120]([C:123]2[CH:128]=[CH:127][C:126]([O:129][CH2:130][CH2:131][CH2:132][O:133][CH2:134][C:135]3[CH:140]=[CH:139][CH:138]=[CH:137][C:136]=3[O:141][CH3:142])=[CH:125][CH:124]=2)[CH:119]([O:143][CH2:144][C:145]2[CH:154]=[CH:153][C:152]3[C:147](=[CH:148][C:149]([OH:155])=[CH:150][CH:151]=3)[CH:146]=2)[CH2:118]1)=[O:116])([CH3:113])([CH3:111])[CH3:112]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccc(OCOCC[Si](C)(C)C)cc3c2)cc1
Agent: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: COc1ccccc1COCCCOc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1OCc1ccc2ccc(OCOCC[Si](C)(C)C)cc2c1
Agent: C[Si](C)(C)CCOCOc1ccc2ccc(CCl)cc2c1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccc(O)cc3c2)cc1

Procedure:
in an analogeous manner as described in Example 95(a) there was obtained from (3RS,4RS)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-1-carboxylic acid tert-butylester [Example 120(g) (α)] and 2-chloromethyl-7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene [Example 6(u)] (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy-phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidin-1-carboxylic acid tert-butylester as a pale yellow oil; MS: 758 (M+H)+. Then, (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidin-1-carboxylic acid tert-butylester was reacted in analogy to Example 95(b) by cleaving of the SEM protecting group to afford (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(7-hydroxy-naphthalen-2-ylmethoxy)-piperidin-1-carboxylic acid tert-butylester [yellow oil; MS: 628 (M+H)+ ] which, on alkylation with 1-(2-chloro-ethyl)-4-methyl-piperazine hydrochloride (1:2) [Chim. Ther. 4, 283 (1969)] in analogy to Example 90(n) gave (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-naphthalen-2-ylmethoxy]-piperidin-1-carboxylic acid tert-butylester as a light brown oil; MS: 754 (M+H)+.
Reaction SMILES: C([Li])(CC)C.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:30]=[CH:29][C:28]2[C@@H:27]3[C@:18]([CH:38]=[CH2:39])([C@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[C@@H:22]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH2:21][CH2:20]4)[CH2:17][CH2:16][C:15]=2[CH:14]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1>C1COCC1>[F:50][C:30]1[C:13]([O:12][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][O:6]2)=[CH:14][C:15]2[CH2:16][CH2:17][C@:18]3([CH:38]=[CH2:39])[C@@H:27]([C:28]=2[CH:29]=1)[CH2:26][CH2:25][C@@:23]1([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]1[O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1
Reactant: C=C[C@@]12CCc3cc(OC4CCCCO4)ccc3[C@H]1CC[C@]1(C)[C@@H](OC3CCCCO3)CC[C@H]12
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C=C[C@@]12CCc3cc(OC4CCCCO4)c(F)cc3[C@H]1CC[C@]1(C)[C@@H](OC3CCCCO3)CC[C@H]12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3 ml of a 1.3 M s-butyllithium solution was added in drops under argon to a solution of 120 mg of 3,17β-bis-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-triene in 4 ml of THF that was cooled to −78° C., it was stirred for 30 minutes and then a solution that consists of 650 mg of N-fluorodibenzenesulfonimide in 4 ml of THF was added in drops while being exposed to continuous cooling. The reaction mixture was stirred first for 1 hour at −78° C. then for another 16 hours while being heated to room temperature. The reaction solution was poured onto ice water, extracted several times with ethyl acetate, the collected organic phases were washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The dark, oily crude product (330 mg) was used in the next stage without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[N+:14]([C:6]1[C:5]2[C:10]([CH:9]=[CH:8][CH:7]=1)=[N:11][C:3](=[O:2])[CH:4]=2)([O-:16])=[O:15]
Reactant: COC(=O)Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1C=c2c([N+](=O)[O-])cccc2=N1
Temperature: 50 °C
Yield: 73.2 %

Procedure:
4.43 g (18.45 mmol) of methyl-(2,6-dinitrophenyl)-acetate is added in 38.8 ml of glacial acetic acid and 11 ml of water and mixed with 3.75 g of iron powder and stirred for four more hours. In this case, heating to 40 to 60° C. takes place. The reaction mixture is added to ice water, mixed with ethyl acetate and vigorously stirred for ten minutes. The mixture is filtered through a glass-fiber filter, the organic phase is separated, and the aqueous phase is extracted twice more with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off after the desiccant is filtered off. The residue is chromatographed on silica gel (mobile solvent methanol/dichloromethane). 2.38 g of 4-nitro-indol-2-one is isolated. The nitro compound is mixed again in glacial acetic acid/water with 2.7 g of iron powder, and the above-described cycle is passed through another time. 1.63 g of the desired amine is isolated.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[CH2:7][OH:8]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:8][CH2:7][CH:6]([CH3:9])[O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[CH:2]=[O:1]
Reactant: CC(CO)Oc1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(CO)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
Manganese dioxide (4.02 g; 26.3 mmol; 5 eq.) was added to a solution of 2-(2-hydroxymethyl-phenoxy)-propan-1-ol (960 mg; 5.3 mmol; 1 eq.) in DCM (50 mL) and the resulting mixture was stirred at room temperature for 1.5 hour. The suspension was filtered through a short plug of Celite®. The solution was washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (705 mg, 74%) as a colourless oil. UPLC/MS: (MS+) 181.1 ([M+H]+).
Reaction SMILES: [O-]CC.[Na+].C(OC(=O)[NH:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[C:19]#[C:20][Si](C)(C)C)C>C(O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][C:14]=1[F:16])[NH:9][CH:20]=[CH:19]2
Reactant: CCOC(=O)Nc1cc(F)c(OC)cc1C#C[Si](C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2cc[nH]c2cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium ethoxide (formed by dissolving NaH 11.45 g, 60% in oil, 286.2 mmol, 4 eq.) in ethanol was poured into an EtOH solution of (5-fluoro-4-methoxy-2-trimethylsilanylethynyl-phenyl)-carbamic acid ethyl ester (22.14 g, 71.55 mmol) in EtOH (250 mL). The reaction was allowed to stir at room temperature for 2 hours and heated to 75° C. overnight. The EtOH was removed in vacuo and the residue diluted with water. The aqueous suspension was extracted 2×300 mL with Et2O. The organics were combined and washed with brine. The organic layer was collected, dried over MgSO4, filtered, and the solvent removed in vacuo leaving a dark red oil. The oil was purified by silica gel flash column chromatography using 15% EtOAc in hexanes as the mobile phase. Removal of the solvent in vacuo from the fractions containing the product left a golden yellow oil which solidified on standing: 1H NMR (300 MHz, CDCl3): 3.93 (s, 3H), 6.48 (m, 1H), 7.15 (m, 3H), 8.11 (bs, 1H); MS(ES+): m/z 166 (M+H)+; MS(ES−): m/z 164 (M−H)−; Calculated for C9H8FNO: C, 65.45; H, 4.88; N, 8.48; found: C, 65.17; H, 4.97; N, 8.70.
Reaction SMILES: CO[C:3]1[CH:19]=[C:18]([NH:20]C)[C:17]([N+:22]([O-])=O)=[CH:16][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](NC)=O)C=1.[CH3:25][CH2:26]O>[Pd]>[N:9]1([CH2:10][CH2:11][CH2:6][O:5][C:4]2[CH:16]=[C:17]([NH2:22])[C:18]([NH2:20])=[CH:19][CH:3]=2)[CH2:8][CH2:12][CH2:26][CH2:25]1
Reactant: CCO
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Agent: [Pd]
Product: Nc1ccc(OCCCN2CCCC2)cc1N
Reaction time: 18 h

Procedure:
To a solution 2-Nitro-4-(3-pyrrolidinylpropoxy)phenylamine 1 in EtOH, Pd/C (0.1 eq) is added. The reaction vessel is repeatedly purged (×3) with nitrogen, and then stirred under a hydrogen atmosphere for 18 h. The product is filtered through a Celite plug, and the plug washed with 25 mL of EtOH, to yield 2. LCMS 236.2 Rt 0.94 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([NH:17][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
49.5 gm (0.24 mol) of 3-methoxy-benzene sulfonic acid chloride were dissolved in 50 ml of tetrahydrofuran, and the solution was added dropwise over a period of 25 minutes to a solution of 40 gm (0.55 mol) of tert. butylamine in 200 ml of tetrahydrofuran. After stirring for 1 hour at room temperature and for 7 hours at 60° C., the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was treated with cyclohexane, yielded 54.1 gm (92.6% of theory) of N-tert. butyl-3-methoxy-benzenesulfonamide.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C1COCC1>[C:1]1([NH:7][C:8]([NH:10][C:12](=[O:13])[O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(NC(=O)Oc1ccc([N+](=O)[O-])cc1)Nc1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of 6.8 g. of phenylurea in 50 ml. of dry THF maintained at 0° C. under nitrogen were added 5.05 g. of p-nitrophenyl chloroformate. The reaction mixture was allowed to warm to room temperture and was stirred for about 18 hours. The mixture was evaporated to dryness and the residue dissolved in ethyl acetate. The solution was washed twice with water, twice with brine, and was filtered through sodium sulfate. The filtrate was evaporated to dryness to yield 4.9 g. of the product as a white product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH3:13])[CH3:2].O.[NH2:18][NH2:19]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH3:13])[NH:19][N:18]=1)=[O:16])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ocnc1C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ocnc2C)[nH]n1
Yield: 50.6 %

Procedure:
A mixture of 2,4-diketo4-(4-methyloxazol-5-yl)butyric acid ethyl ester (8.50 g), hydrazine hydrate (1.88 g), and ethanol (100 ml) was refluxed for 3 hours and concentrated. The residue was chromatographed (silica gel, Hex/EtOAc 1/1) to yield 4.20 g of 3-ethoxycarbonyl-5-(4-methyloxazol-5-yl)pyrazole as tan solids, mp 131°-133° C. (methanol/isopropyl ether). NMR: 1.42 (t, 3H), 2.48 (s, 3H), 4.44 (q, 2H), 7.05 (s, 1H, 4-pyrazolyl H), 7.85 (s, 1H, 2-oxazolyl H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([N:14]=[CH:15][C:16]([NH2:20])=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:28](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:29]>C(Cl)Cl>[N:20]([C:16]1[CH:15]=[N:14][C:13]2[C:18](=[CH:19][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[N:17]=1)=[C:28]=[S:29]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1ccc2ncc(N)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(N=C=S)nc2c1
Yield: 19.3 %

Procedure:
A mixture of 7-methoxyquinoxalin-2-amine 2,2,2-trifluoroacetate (578 mg, 2 mmol), triethylamine (335 μL, 2.400 mmol), and 1,1′-thiocarbonyldipyridin-2(1H)-one (557 mg, 2.400 mmol) was stirred in 5 mL DCM for 24 h. The reaction was directly eluted on a 120 g silica gel cartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min to afford 2-isothiocyanato-7-methoxyquinoxaline (84 mg, 0.387 mmol, 19% yield).
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11](F)[C:8]=1[C:9]#[N:10]>>[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([O:4][CH2:3][C@H:2]([NH2:1])[CH3:5])[C:8]=1[C:9]#[N:10]
Reactant: C[C@@H](N)CO
Reactant: N#Cc1c(N)cccc1F
Product: C[C@@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (R)-2-aminopropan-1-ol and 2-amino-6-fluorobenzonitrile as brown solid (81%). 1H NR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H), 5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t, J=8.3 Hz, 1H). MS 192 (MH+).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O>O1CCOCC1.C(OCC)(=O)C>[CH3:2][C:1]1[S:3][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Add thioacetamide (0.09 g, 1.2 mmol) to a solution of 2-bromoacetophenone (0.2 g, 1.0 mmol) in 30 mL dioxane. Stir at room temperature for 4 hours, dilute with ethyl acetate, wash sequentially with aqueous sodium carbonate (3×15 mL) and water (3×20 mL). Dry the organic phase over sodium sulfate, concentrate under reduced pressure, and subject the residue to silica gel chromatography, eluting with hexane containing 10% ethyl acetate to provide the desired compound in 78% yield. MS(ES+): m/z=176.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(N)cc2)CC1

Procedure:
4.3 g (19.5 mmol) 1-methyl-4-(4-nitro-phenyl)-piperidine are dissolved in a mixture of 60 ml of ethanol and 60 ml THF, combined with 2 g palladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Then the reaction mixture is suction filtered and the filtrate is concentrated by evaporation. Yield: 3.5 g
Reaction SMILES: C=O.[C:3](B)#N.[Na].C(#N)C.[F:10][C:11]1[CH:12]=[C:13]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH3:24])[CH2:19][CH2:18]1>CO>[CH3:24][N:23]([CH3:3])[CH:20]1[CH2:19][CH2:18][N:17]([C:16]2[CH:15]=[CH:14][C:13]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:12][C:11]=2[F:10])[CH2:22][CH2:21]1
Reactant: BC#N
Reactant: CNC1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
Formaldehyde (37% aq. sol., 0.4 ml) and sodium cyanoboron hydride (138 mg) were successively added to an acetonitrile suspension (3 ml) of 400 mg of the (S)-N-{3-[3-fluoro-4-(4-methylamino-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 70) which was synthesized in Example 18, and the mixture was stirred at room temperature for 48 h. Methanol was added and the mixture was stirred for 10 min. Thereafter, alumina (5 g) was added and the residue was evaporated under vacuum. The residue was purified by alumina column chromatography (solvent: chloroform/methanol=100/1) to afford the title compound (363 mg) in a yield of 87%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccccc3F)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
0.29 g of 2-fluoro-benzoic acid (2.03 mmol) and 0.7 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.03 mmol) were dissolved in 25 ml of dichloromethane. 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) were added at 0° C. and the reaction mixture was stirred for 16 h at room temperature. 25 ml of dichloromethane were added, the organic layer washed with aqueous saturated sodium chloride, the aqueous phase re-extracted once with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5%). Fractions containing the product were combined. The solvent was evaporated to yield 0.84 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1)=O.Cl.[N:13]1[O:14][N:15]=[C:16]2[CH:21]=[C:20]([CH2:22][O:23][NH2:24])[CH:19]=[CH:18][C:17]=12.N1C=CC=CC=1>C(O)C>[N:13]1[O:14][N:15]=[C:16]2[CH:21]=[C:20]([CH2:22][O:23][N:24]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=3)[CH3:1])[CH:19]=[CH:18][C:17]=12
Reactant: NOCc1ccc2nonc2c1
Reactant: CC(=O)c1ccc(O)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NOCc1ccc2nonc2c1)c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 3-fluoro-4-hydroxyacetophenone (0.061 g, 0.398 mmol), (benzo[c][1,2,5]oxadiazol-5-yl)methoxyamine hydrochloride (0.095 g, 0.470 mmol) and pyridine (0.13 ml, 1.61 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with water. The resultant suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to an off-white solid. The crude product was purified by column chromatography (SiO2), eluting with 9:1 petrol/ethyl acetate, to give a pale beige solid which was further washed with petrol/dichloromethane to give 3′-fluoro-4′-hydroxyacetophenone-O-[(benzo[c][1,2,5]oxadiazol-5-yl)methyl]oxime (CP9-128) as a pale beige solid (0.098 g, 82%), m.p. 139-140°.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C:27]([CH:34]=O)=[N:26]1>CO.N1CCCCC1>[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ncccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0442 g, 0.133 mmol) synthesized in Example B45, Step 3 in methanol (3 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (0.0206 g, 0.140 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0292 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH2:11])[CH2:6]1)=[O:4].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:6][C@H:7]([NH:11][C:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:18])[C@@H:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: O=C(O)c1cccs1
Reactant: COC(=O)[C@@H]1C[C@H](N)[C@@H](O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2cccs2)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a stirred solution of the (1R,3S,4S)-3-amino-4-hydroxy-cyclopentanecarboxylic acid methyl ester (300 mg) at r.t. in DMF (7.0 ml) under an argon atmosphere were added N-ethyldiisopropylmine (0.96 ml), 2-thiophene carboxylic acid (314 mg) and BOP (1.04 g). The mixture was then stirred at r.t. for 19 h. The clear brown solution was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give (1R,3S,4S)-3-hydroxy-4-[(thiophene-2-carbonyl)-amino]-cyclopentanecarboxylic acid methyl ester as light brown gum. MS: 270.3 ([M+H]+).