Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)[CH3:2].F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.O.OC1C2N=NNC=2C=CC=1.[C:46]([NH:49][NH2:50])(=[O:48])[CH3:47].C(N(C(C)C)C(C)C)C>ClCCl.O>[C:46]([NH:49][NH:50][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]([O:13][CH3:14])=[N:5][C:6]=1[CH3:12])(=[O:48])[CH3:47]
Reactant: CCc1cc(C(=O)O)c(C)nc1OC
Reactant: CC(=O)NN
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C(=O)NNC(C)=O)c(C)nc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 143.5 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask, 5-ethyl-6-methoxy-2-methyl-nicotinic acid (500 mg, 2.56 mmol) of Step 2, Example 14 is dissolved in dichloromethane (30 mL). O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (990 mg, 3.33 mmol) is added, followed by hydroxybenzotriazole hydrate (510 mg, 3.33 mmol). The resulting mixture is stirred at rt for 45 min to give a suspension, which is treated with acetic hydrazide (285 mg, 3.85 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol). The resulting solution is stirred at rt for 32 hr, LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with six portions of dichloromethane, the combined extract is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:1, increasing to 1:2). Fractions containing the product are combined and evaporated to obtain 5-ethyl-6-methoxy-2-methyl-nicotinic acid N′-acetylhydrazide (give 923 mg) as a white solid. MS: m/e=252 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.72 (1H, d), 8.50 (1H, d), 7.49 (1H, s), 3.96 (3H, s), 2.59 (3H, s), 2.54 (2H, q), 2.12 (3H, s), 1.17 (3H, t).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:14](O)=[O:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:17]=[CH:18][CH:19]=[N:20][C:5]1=2.Cl.C([N:24]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N.C(=O)(O)[O-].[Na+]>ClCCl.O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:14]([NH2:24])=[O:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:17]=[CH:18][CH:19]=[N:20][C:5]1=2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCN1c2cc(C(=O)O)ccc2Sc2nccnc21
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCN1c2cc(C(N)=O)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
1.04 g of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)carboxylic acid was dissolved in a mixture of dichloromethane (20 ml) with tetrahydrofuran (20 ml) in a nitrogen atmosphere. Under ice-cooling, 1.04 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 200 mg of 1-hydroxybenzotriazole were added thereto and the resulting mixture was stirred at room temperature for 30 minutes. After blowing ammonia gas thereinto, the reaction mixture was distributed into an aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were filtered. Further, the aqueous layer was acidified and the starting materials were recovered. After repeating the above-mentioned procedures, the title compound (620 mg in total) was obtained as yellow crystals.
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.O1C=CC=C1S(Cl)(=O)=O>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: O=S(=O)(Cl)c1ccco1
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (259 mg, 1.1 mmol) and 2-furanylsulfonyl chloride (209 mg, 1.2 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give benzamide I-8 (248 mg, 61%) as a white powder: mp (EtOAc) 178-180° C.; 1H NMR δ 10.40 (s, 1H, CONH), 8.93 (d, J=2.2 Hz, 1H, H-2″), 8.69 (t, J=6.2 Hz, 1H, NHSO2), 8.31 (dd, J=4.7, 1.5 Hz, 1H, H-6″), 8.19 (ddd, J=8.3, 2.5, 1.5 Hz, 1H, H-4″), 7.94 (dd, J=1.8, 0.9 Hz, 1H, H-5′), 7.92 (br dd, J=8.3, 1.6 Hz, 2H, H-2, H-6), 7.37-7.43 (m, 3H, H-3, H-5, H-5″), 7.08 (dd, J=3.4, 0.9 Hz, 1H, H-3″), 6.65 (dd, J=3.4, 1.8 Hz, 1H, H-4″), 4.20 (d, J=6.2 Hz, 2H, CH2N); 13C NMR δ 165.5, 148.8, 146.8, 144.5, 141.9, 141.7, 135.7, 133.0, 127.7 (2), 127.2 (3), 123.4, 115.5, 111.3, 45.4; MS m/z 378.5 (MH+, 100%). Anal. calcd for C17H15N3O4S: C, 57.13; H, 4.23; N, 11.76. Found: C, 57.40; H, 4.19; N, 11.74%.
Reaction SMILES: C(O)C.[Cl-].[NH4+].[O:6]=[C:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([Cl:19])=[C:12]([N+:16]([O-])=O)[CH:13]=2)[NH:8]1>[Fe].O>[O:6]=[C:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([Cl:19])=[C:12]([NH2:16])[CH:13]=2)[NH:8]1
Reactant: O=C1Cc2cc([N+](=O)[O-])c(Cl)cc2N1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc2c(cc1Cl)NC(=O)C2
Yield: 93.1 %

Procedure:
To a mixture of ethanol (200 ml) and water (40 ml) were added ammonium chloride (2.2 g) and iron metal (19.7 g). To the mixture was added 2-oxo-5-nitro-6-chloroindoline (12.5 g) at 60° C. After refluxing for 45 minutes, the reaction mixture was filtered under warm condition. The filter cake was washed with ethanol. The combined filtrate and washings were evaporated to dryness under reduced pressure to give 2-oxo-5-amino-6-chloroindoline (10.0 g)
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:3]1[C:4]2=[N:9][CH:8]=[CH:7][CH:6]=[C:5]2[N:1]=[CH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: c1cnc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1cnc2cccnc21)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a brown solution of 4-azabenzimidazole (4.75 g) in DMF (80 mL) was added benzyl bromoacetate (6.58 mL) followed by Cs2CO3 (25.9 g). The resulting light brown suspension was stirred overnight. The reaction mixture was diluted with EA and washed twice with water and aq. sat. NH4Cl. The aq. layers were extracted twice with EA. The combined org. layers were dried over MgSO4, filtrated off and evaporated in reduced pressure. The crude was purified by CC (Biotage, SNAP 100 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in % B: 0 to 5 over 3CV, 5 for 5CV, 5 to 15 over 5CV, 15% B for 3CV) to afford 4.99 g of the desired compound as yellow solid. LC-MS (C): tR=0.59 min; [M+H]+: 267.86.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][C@@:4]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:15][CH2:14][N:13]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:12]2)[CH2:6][CH2:5]1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCNC2)C(=O)O1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCN(c3ccc(C(F)(F)F)cn3)C2)C(=O)O1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-pyrrolidin-3-yl)-1,3-oxazinan-2-one and 2-fluoro-5-trifluoromethylpyridine at 150° C. for 20 min. LC-MS Method 1 tR=1.51 min, m/z=464(M+1); 1H NMR (CD3OD) 8.26(s, 1H), 8.00(d, 1H), 7.38(m, 4H), 7.29(m, 1H), 7.01(m, 1H), 4.74(m, 1H), 3.77(m, 2H), 3.58(q, 1H), 3.47(m, 1H), 2.83(m, 1H), 2.55(m, 2H), 2.18(s, 2H), 1.24(s, 3H), 0.94(s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][O:34][C:35](=[O:86])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][CH:50]=[C:51]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[C:63]([Cl:65])[C:62]([NH:66][C:67]([C:69]4[CH:70]=[N:71][C:72]([N:75]5[CH2:80][CH2:79][NH:78][CH2:77][C@H:76]5[CH3:81])=[CH:73][CH:74]=4)=[O:68])=[CH:61][C:60]=3[C:82]([F:85])([F:84])[F:83])=[CH:55][CH:54]=2)[N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:33][O:34][C:35](=[O:86])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][CH:50]=[C:51]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[C:63]([Cl:65])[C:62]([NH:66][C:67]([C:69]4[CH:70]=[N:71][C:72]([N:75]5[CH2:80][CH2:79][N:78]([C:5]([C@H:3]6[CH2:4][C:2]6([CH3:8])[CH3:1])=[O:6])[CH2:77][C@H:76]5[CH3:81])=[CH:73][CH:74]=4)=[O:68])=[CH:61][C:60]=3[C:82]([F:84])([F:85])[F:83])=[CH:55][CH:54]=2)[N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: CC1(C)C[C@@H]1C(=O)O
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: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylic acid in DMA (28.9 μL, 0.015 mmol;). and HATU (8.25 mg, 0.022 mmol) dissolved in DMA (0.5 mL), was added ((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 3 TFA (16 mg, 0.014 mmol; Preparation 53) and N,N-diisopropylethylamine (25.2 uL, 0.15 mmol) and the reaction mixture was stirred at RT overnight, concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the title compound (8.6 mg) as the di-TFA salt. (m/z): [M+H]+ calcd for C44H50ClF3N8O5 863.35 found 863.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][Si:10]([CH3:17])([CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C@H:44]([NH:46][CH2:47][C:48]1[CH:57]=[CH:56][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:50][CH:49]=1)[CH3:45].CCN(C(C)C)C(C)C>C(Cl)Cl.[Cl-].[Na+].O>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C@H:44]([N:46]([CH2:47][C:48]1[CH:49]=[CH:50][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:56][CH:57]=1)[C:13]([C@H:12]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][Si:10]([CH3:17])([CH3:16])[CH2:11]1)=[O:15])[CH3:45]
Reactant: COC(=O)c1ccc(CN[C@H](C)c2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1C[Si](C)(C)C[C@H]1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CN(C(=O)[C@@H]2C[Si](C)(C)CN2C(=O)OC(C)(C)C)[C@H](C)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid (0.25 g, 0.96 mmol) in DCM (5 mL) were added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (0.60 g, 2.2 mmol) and a solution of (R)-methyl 4-(((1-(2-fluorophenyl)ethyl)amino)methyl)benzoate (250 mg, 0.87 mmol) in DCM (2 mL) followed by DIEA (0.30 mL, 1.74 mmol). The resulting suspension was stirred at rt overnight and diluted with DCM and brine. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (87 mg, 19%). MS(ESI+) m/z 529.3 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][CH:12]=[CH:13][C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=CCc1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCc1cccc2ccccc12
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of 4-(1-naphthyl)butenoic acid (3.96 g) in ethyl alcohol (45 cm3) was added palladium on carbon (10%, 400 mg). The mixture was stirred under hydrogen (approx. 2 atm) for 3 h. The catalyst was then removed by filtration through a pad of Dicalite® and the solvent was removed under reduced pressure to yield the title compound (3.59 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:22][C:23]([NH2:25])=[NH:24].[ClH:26].C[O-].[Na+]>CO.O>[NH2:24][C:23]([NH2:25])=[N:22][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:11][C:2]=1[CH3:1].[ClH:26]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N2CCCCC2)cc1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(N2CCCCC2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 1 h

Procedure:
A solution of 20 g of methyl 2-methyl-4-piperidino-5-methylsulfonylbenzoate [obtainable by reacting piperidine with 2-methyl-4-chloro-5-methylsulfonylbenzoic acid followed by esterification] and 30 g of guanidine, which has been liberated beforehand from the guanadine hydrochloride using sodium methylate, is stirred in 160 ml of methanol at 50° over a period of twenty hours. After cooling to 0°, water is added, stirring is continued for 1 hour and the precipitate which forms is separated off. Recrystallization from dichloromethane/methanol gives N-diaminomethylene-2-methyl-4-piperidino-5-methylsulfonylbenzamide, m.p. 222°-224°, hydrochloride m.p. 275°-276°.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29](OC(N1CCN(CC2C=CC(OCCCN3CCCCC3)=CC=2)CC1)=O)(C)([CH3:31])[CH3:30]>CC(C)=O>[CH:29]([N:26]1[CH2:27][CH2:28][CH:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:8])[CH2:14][CH2:13]3)=[CH:17][CH:18]=2)[CH2:24][CH2:25]1)([CH3:31])[CH3:30]
Reactant: O=C(c1ccccc1)N1CCN(Cc2ccc(OC3CCNCC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Solvent: CC(C)=O
Product: CC(C)N1CCC(Oc2ccc(CN3CCN(C(=O)c4ccccc4)CC3)cc2)CC1

Procedure:
The title compound (E33) was prepared from 1-phenyl-1-{4-[4-(piperidin-4-yloxy)-benzyl]-piperazin-1-yl}-methanone (E32) and acetone using the method described in Description 1 (D1). MS(ES+) m/e 422 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([CH3:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([CH3:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Yield: 89.4 %

Procedure:
A mixture of 0.30 g of ethyl 1-(3-chloro-2-pyridinyl)-3-methyl-1H-pyrazole-5-carboxylate, 5 ml of methanol and 5 ml of a 2N aqueous sodium hydroxide solution was heated to reflux for 3 hours. After the reaction mixture was allowed to cool, water was poured and the aqueous layer was washed with methyl t-butyl ether two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with methyl t-butyl ether three times. The combined organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.24 g of 1-(3-chloro-2-pyridinyl)-3-methyl-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[CH:27][N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:41][O:42][C:43]([CH3:49])([CH3:48])[C:44]([NH:46][OH:47])=[O:45]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:41]/[O:42][C:43]([C:44](=[O:45])[NH:46][OH:47])([CH3:49])[CH3:48])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[C:30]([C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([OH:38])[CH:32]=4)=[CH:29][N:28]=[CH:27][N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NO
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4ncncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3ncncc3-c3ccc(O)c(O)c3)CS[C@H]12)c1csc(N)n1)C(=O)NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.3 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4dihydroxyphenyl)-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (90 mg) (0.15 mmol) and 34 mg (0.2 mmol) of 2-(aminooxy)-N-hydroxy-2-methylpropionamide hydrochloride are dissolved in 2 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the mixture is concentrated in a high vacuum at room temperature and the residue is crystallized from ethanol/diethyl ether. It is filtered off under suction and washed with ether and water. After drying in a high vacuum at room temperature there are obtained 72 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(hydroxycarbamoyl)-1-methylethoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:7][CH:8]=1.NN>C(O)C.C(Cl)(Cl)Cl>[NH2:16][CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cccc(C2CCCN2CCN)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[2-(3-methoxyphenyl)-1-pyrrolidinyl]ethyl}-1H-isoindole-1,3(2H)dione (0.92 g) in ethanol (30 ml) and chloroform (5 ml) was added anhydrous hydrazine (98%, 0.42 ml) at ambient temperature, under nitrogen. The reaction mixture was warmed under reflux for 1.5 hrs, cooled to ambient temperature, and filtered. The filter cake was washed with ethanol and the combined filtrates were concentrated. The residue was diluted with dichloromethane/ether. The organic solvents were decanted and concentrated to give N-(2-aminoethyl)-2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].Cl>[Pd].CO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(O)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC(c2cccc(O)c2F)CC1

Procedure:
Preparation according to preparation 18: 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenol (1.1 g, 4.97 mmol), methanol (20 ml), palladium on carbon (0.26 g) and hydrochloric acid (0.2 ml, conc). Yield: 1.1 g. MS m/z (relative intensity, 70 eV) 223 (M+, 32), 222 (17), 209 (13), 208 (bp) 84 (20).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[C:19]3[C:10]([N:11]=[C:12]4[C:17](=[C:18]3O)[CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:18]1[C:19]2[C:10]([N:11]=[C:12]3[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:20]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c2c(nc3ccc(C4CCCCC4)cc13)CCCC2
Product: Clc1c2c(nc3ccc(C4CCCCC4)cc13)CCCC2

Procedure:
7-Cyclohexyl-9-hydroxy-1,2,3,4-tetrahydroacridine (15.539 g) was refluxed for 45 minutes in 100 mL of POCl3. At the end of this time the reaction mixture was concentrated under reduced pressure and the residue was distributed between water and ether. Aqueous ammonia was added portionwise with shaking until all the organic material was dissolved in the ether layer. Evaporation and recrystallization of the residue from methanol gave 14.81 g of analytically pure product, mp 89°-91° C.
Reaction SMILES: C(O[K])(C)(C)C.[CH3:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.[OH:13][CH:14]([CH2:17][OH:18])[CH2:15]Br.Cl>C(O)(C)(C)C.O1CCCC1>[OH:13][CH:14]([CH2:17][OH:18])[CH2:15][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[CH3:7]
Reactant: Cc1ncc[nH]1
Reactant: OCC(O)CBr
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1nccn1CC(O)CO
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A200 ml flask was charged with 2.0 g of t-butoxypotassium, 70 ml of tetrahydrofuran, 1.23 g of 2-methylimidazole. After stirring for 30 minutes, a solution of 2.5 g of 2,3-dihydroxyl-n-propyl bromide in 5 ml of t-butanol was added. After refluxing for one hour, 5 ml of 1 N HCl solution was added and the mixture was allowed to stand over night. The solvent was evaporated under reduced pressure. The residue was extracted with dichloromethane, washed with saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (development solvent: methyl acetate/methanol=90/10) to obtain 1.9 g of 1-(2′,3′-dihydroxylpropyl)-2-methylimidazole (compound (A-1)). 1H-NMR spectrum of the resulting compound is shown in FIG. 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[C:19]([Cl:26])[CH:18]=1>CCCCC.ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:14][C@H:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:25])=[C:19]([Cl:26])[CH:18]=1
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Reactant: O=C=Nc1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: CCCCC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccc(Br)cc2Cl)[C@H](c2ccccc2)O1
Yield: 87.2 %

Procedure:
To a stirred or shaken solution of 157 mg (0.76 mmol) of (4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-amine (abbreviated as (4S,5S)-amine 1) in pentane (3.5 mL) was added dropwise a solution of 169 mg (0.73 mmol) of 4-bromo-2-chlorophenyl isocyanate in dichloromethane (0.7 mL). A white precipitate was observed after stirring for 0.5 to 2 h. The precipitate was collected, rinsed with pentane, and dried under vacuum to yield 280 mg (88%) of the title compound. In some examples, pentane was used to dissolve the required isocyanate rather than dichloromethane. In addition, if the required isocyanate was a liquid, it was added dropwise as a neat liquid on small-scale reactions such as this. In cases where a precipitate was not observed or the precipitate was not of sufficient purity, the solvent was evaporated, and the residue was purified by column chromatography (hexanes/ethyl acetate) to yield the desired product.