Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[CH:20][C:15]3[N:16]=[C:17]([NH2:19])[O:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH2:22]1[O:31][C:30]2[C:25](=[C:26]([C:32](O)=[O:33])[CH:27]=[CH:28][CH:29]=2)[O:24][CH2:23]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[CH:20][C:15]3[N:16]=[C:17]([NH:19][C:32]([C:26]4[C:25]5[O:24][CH2:23][CH2:22][O:31][C:30]=5[CH:29]=[CH:28][CH:27]=4)=[O:33])[O:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N)oc3c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(NC(=O)c4cccc5c4OCCO5)oc3c2)ccn1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
4-(2-Amino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (1 eq) and 2,3-dihydro-1,4-benzodioxane-5-carboxylic acid (1 eq) were dissolved in DMF. To this solution were added DIPEA (3 eq) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (1 eq). The mixture was stirred at 40° C. overnight, then diluted with ethyl acetate and washed once each with 1N HCl, saturated aqueous sodium bicarbonate, and brine, and finally dried with anhydrous sodium sulfate, filtered, and concentrated. This was purified by preparatory reverse phase HPLC. MH+=447.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C(=O)(O)[O-].[Na+]>C(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=1)[N:5]=[CH:4][C:3]([C:17]#[N:18])=[C:2]2[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([Br:19])[CH:21]=1)([O-:14])=[O:13]
Reactant: COc1cc([N+](=O)[O-])cc2c(Cl)c(C#N)cnc12
Reactant: Nc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc([N+](=O)[O-])cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 75.8 %

Procedure:
A mixture of 1.9 g (7.6 mmol) of 4-chloro-8-methoxy-6-nitro-quinoline-3-carbonitrile and 0.86 ml (8.3 mmol) of 3-bromo aniline in 95 ml ethanol was refluxed under nitrogen for 5 hours. The reaction mixture was poured into diluted sodium bicarbonate solution. Ethanol was removed under vacuum. The mixture was diluted with ethyl acetate and the organic layer was separated and dried over sodium chloride. The solution was concentrated and solid was collected and then washed with hexane. Upon drying, 2.3 g of yellow solid obtained: mass spectrum (electrospray, m/e) M+H 398.8 and 400.8.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Product: CS(=O)(=O)Nc1ccc(Br)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the reaction of 4-bromo-3-(trifluoromethyl)aniline with methanesulfonyl chloride as described in Example 45, Part A.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:23])=[CH:11][C:12]([N+:20]([O-])=O)=[C:13]([CH:19]=1)[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.[Cl-].[NH4+]>C1COCC1>[NH2:20][C:12]1[CH:11]=[C:10]([F:23])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][C:13]=1[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(OCc2ccccc2)c(F)cc1N
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a solution of 5-benzyloxy-4-fluoro-N,N-dimethyl-2-nitrobenzamide (1.06 g) in THF (3 mL) were added ethanol (12 mL) and water (1.5 mL), and to the solution were added ammonium chloride (893 mg) and reduced iron (933 mg). The resultant mixture was heated under reflux for 2 hours, allowed to stand for cooling to room temperature, and filtered through a Celite. The filtrate was concentrated and the residue was diluted with ethyl acetate. The extract was washed with successively with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over sodium sulfate, and concentrated to give 2-amino-5-benzyloxy-4-fluoro-N,N-dimethylbenzamide (984 mg) as a crude product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH3:26][O:27][CH2:28][O:16][C:3]1[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:7][C:2]=1[Br:1]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 45 °C
Yield: 95.4 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D 2.54 g, 8.88 mmol) and catalytic amount of Bu4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ 7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH3:19])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:13]=2[CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH3:19])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:13]=2[CH:28]=1)(=[O:7])[CH3:6]
Reactant: CCCc1nc2ccc(N)cc2n1Cc1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2ccc(NC(C)=O)cc2n1Cc1ccccc1Cl
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Acetic anhydride (62 mg) was added to a solution of 150 mg of 6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole and 61 mg of triethylamine in 3 ml of methylene chloride at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was washed with water, and was then dried. The solvent was distilled off under reduced pressure. The residue was crystallized with ether to give 143 mg of 6-acetylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (89).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:12]=[CH:11][C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:14](#[N:16])[CH3:15].N[C@H](CO)C.C(OCC)(=O)C>N1C=CC=CC=1>[S:1]([N:16]1[CH2:15][CH2:14]1)([C:4]1[CH:12]=[CH:11][C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CC#N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: C[C@H](N)CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 100 gallon glass-lined vessel, fitted with mechanical stirrer, addition funnel, nitrogen inlet and temperature probe, was charged with nosylchloride (52.7 kg) and acetonitrile (75L) at room temperature under nitrogen. The slurry was cooled to about 0° C. A solution of L-alaninol (7) (7.5 kg) in pyridine (32L) was added over about an hour maintaining the reaction temperature less than 10° C. during the addition, and then the mixture was aged for about two hours at about 3° C. to 5° C. Ethyl acetate (188L) and water (75L) were added and the phases were mixed. The lower aqueous layer was removed and the organic layer was washed with 1M citric acid (2×37.5L) and water (37.5L). The organic layer was cooled to about 15° C. and water (37.5L) was added. Hunig's base (N,N-diisopropylethylamine) (27L) was added for over 30 minutes. The two-phase mixture was aged at 20° C. for about an hour to complete the cyclization, and then the lower aqueous layer was removed and extracted with ethyl acetate (37.5L). The combined organic solutions were washed with 1M citric acid (2×37.5L) and water (2×37.5L). The organic layer was dried by concentration at reduced pressure and temperature at about 15° C.˜20° C. with concurrent addition of isopropylacetate (IPAC) to maintain the constant volume at about 100L. The solvent switch was completed when EA level was <5% by GC or HPLC analysis. The slurry was cooled to about 3° C. for an hour and then filtered. The cake was washed with IPAC (30L) and the solid was dried in air, which afforded about 84% isolated yield for the compound (8) (23.7 kg, 97 wt %).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:65])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:24]([O:59][CH3:60])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:57][CH3:58])[C@@H:34]([CH3:56])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:98]=[C:99]1[CH:103]=[CH:102][C:101](=[O:104])[N:100]1[CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][C:110]([NH:112][NH2:113])=[O:111]>CN(C=O)C>[O:104]=[C:101]1[CH:102]=[CH:103][C:99](=[O:98])[N:100]1[CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][C:110]([NH:112][NH:113][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:65])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:24]([O:59][CH3:60])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:57][CH3:58])[C@@H:34]([CH3:56])[C:35]([NH:37][C@@H:38]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:111]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 mg (11 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 4000 μl of DMF and then admixed with 6.3 mg (33 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4.5 mg (33 μmol) of 1-hydroxy-1H-benzotriazole hydrate, 5.7 μl of N,N-diisopropylethylamine and with 11.5 mg (44 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT overnight and then concentrated under high vacuum. The remaining residue was purified by means of preparative HPLC. Thus, 2.6 mg (14% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[F:15][C:16]1[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]>CC(O)C.Cl.O1CCOCC1>[F:15][C:16]1[C:17]([NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=4[CH:14]=3)[N:28]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCOC(=O)N3C)ncc1Cl
Temperature: 120 °C

Procedure:
A mixture of 2-amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 3-fluoro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in IPA (3 mL) was treated with 4 drops of 4N HCl/dioxane and microwave-heated at 120° C. for 90 minutes. The mixture was concentrated and purified by semipreparative HPLC to afford 3-fluoro-2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.08 (s, 1H), 7.30 (m, 5H), 6.91 (d, 2H), 6.10 (bq, 1H), 4.41 (t, 2H), 3.35 (s, 3H), 2.92 (d, 3H), 2.81 (t, 2H); MS (m/e) 471 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc(OC)c1OC

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 3,4,5-trimethoxyaniline (93.7 mg, 0.51 mmol). The title compound was obtained as a yellow solid (71.0 mg, 32% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.45 (1H, m), 9.01 (2H, m), 8.68 (1H, m), 7.06 (2H, m), 3.32 (9H, s). MS m/z: 514.19, 516.12 [M+H]+.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:9]([S:13]([C:15]1[C:23]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[N+:28]([O-])=O)=[O:14])[CH2:10][CH2:11][CH3:12].Cl.S(=O)=O.[OH-].[Na+]>O>[NH2:28][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([S:24](=[O:26])(=[O:27])[NH2:25])[C:15]=1[S:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[O:14])[C:19]([OH:21])=[O:20]
Reactant: CCCCS(=O)c1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: O=S=O
Solvent: O
Product: CCCCS(=O)c1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
To a solution of sodium dithionite (7.3 g) in water (50 ml) conc. aqueous ammonia (25 ml) was added, after which 4-n-butylsulphinyl-3-nitro-5-sulphamyl-benzoic acid (4 g) was added in portions at 25° C, while stirring. The reaction mixture was heated on a steam bath for 30 minutes. Then 4N hydrochloric acid was added until a pH of 1, while the heating was continued. After the evolution of sulphur dioxide had ceased, the reaction mixture was adjusted to a pH of 2.5 by addition of 2N sodium hydroxide, and cooled. The precipitated 3-amino-4-n-butylsulphinyl-5-sulphamyl-benzoic acid was collected by suction, recrystallized from aqueous ethanol, and dried in vacuo at 115° C. The acid was obtained with a melting point of 237° C (decomp.).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].BrCC.[Mg].O=C1[O:14][C:13](=O)[C:12]2([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:11]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[O:14]=[C:13]([C:12]1([NH:11][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH2:1][CH3:2]
Reactant: CCOC(=O)N1CCC2(CC1)C(=O)OC(=O)N2c1ccccc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)CC)CC1
Reaction time: 1 h

Procedure:
A Grignard-complex, ethyl magnesium bromide, is prepared in the conventional manner, starting from 10.57 parts of 1-bromoethane and 2.14 parts of magnesium in 27 parts of dry tetrahydrofuran. This complex is added dropwise to a warm suspension of 25.7 parts of ethyl 2,4-dioxo-1-phenyl-3-oxa-1,8-diazaspiro[4,5]decane-8-carboxylate in 213 parts of dry tetrahydrofuran: exothermic reaction. Upon completion, stirring is continued for 1 hour at room temperature. After cooling, the reaction mixture is decomposed by dropwise addition of an ammonium chloride solution. The layers are separated and the aqueous phase is extracted with 1,1'-oxybisethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding ethyl 4-(1-oxopropyl)-4-(phenylamino)-1-piperidinecarboxylate as a residue.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH:8]=[CH:9][C:10]=1[NH2:11])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(NC2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1cc(NC2CCN(C)CC2)ccc1N
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A mixture of 1.49 g of (3-isopropoxy-4-nitrophenyl)(1-methylpiperidin-4-yl)amine and 150 mg of 10% palladium-on-carbon in 60 ml of ethanol is hydrogenated at 25° C. under 1 bar for 3 h. The mixture is filtered on Clarcel and the Clarcel is rinsed with ethanol. The filtrate is concentrated to dryness under reduced pressure and the residue is purified by chromatography on a 70 g silica cartridge, elution being carried out with a 96.5/3/0.5 v/v/v dichloromethane/methanol/28% aqueous ammonia mixture at a flow rate of 50 ml/min, so as to obtain 0.9 g of 2-isopropoxy-N4-(1-methylpiperidin-4-yl)benzene-1,4-diamine in the form of a brown liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:24][O:25][C:26]1[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([CH2:33][S:34]([C:36]2[N:40]([CH2:41]O)[C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[N:37]=2)=[O:35])[C:27]=1[CH3:47].[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH2:41][N:40]1[C:39]2[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=2[N:37]=[C:36]1[S:34]([CH2:33][C:28]1[C:27]([CH3:47])=[C:26]([O:25][CH3:24])[C:31]([CH3:32])=[CH:30][N:29]=1)=[O:35])=[O:6]
Reactant: CN(C)CCC(=O)O
Reactant: COc1c(C)cnc(CS(=O)c2nc3ccccc3n2CO)c1C
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3ccccc3n2COC(=O)CCN(C)C)c1C
Temperature: -10 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N,N-dimethyl-β-alanine (0.76 g 0.005 mol) and N-methyl morpholine (0.99 g 0.01 mol) was added to CH2Cl2 (15 ml). The solution was cooled to -10° C. and isobutylchloroformate, (0.68 g 0.005 mol) dissolved in CH2Cl2 (15 ml), was added under inert atmosphere. The solution was stirred for about 20 min at -10° C. [2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazol-1-yl]methanol dissolved in CH2Cl2 (15 ml) was added dropwise to the mixed anhydride at -10° C. The solution was stirred 2 h at -10°, and the temperature was thereafter raised to room temperature. NaOH solution (25 ml 0.24) was added under stirring and the mixture was stirred for about 5 min. After separation the CH2Cl2 phase was dried over Na2SO4, filtered and the solution was evaporated off, giving the desired compound (yield 0.7 g 32%). The identity of the title compound was confirmed with NMR.
Reaction SMILES: C1(OP(O)OC2C=CC=CC=2)C=CC=CC=1.[CH:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=1.[NH:27](C(OCC1C=CC=CC=1)=O)[CH2:28][C:29](O)=[O:30]>N1C=CC=CC=1>[N+:23]([C:22]1[CH:21]=[CH:20][C:19]([O:26][C:29](=[O:30])[CH2:28][NH2:27])=[CH:18][CH:17]=1)([O-:25])=[O:24]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: OP(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 75 %

Procedure:
A mixture of 2.93 g. (0.0125 mole) of phosphorous diphenyl ester and 3.37 g. (0.0125 mole) of mercuric chloride was refluxed for 1 hour in 20 ml. of pyridine. Thereafter, 1.74 g. (0.0125 mole) of p-nitrophenol and 10 ml. of pyridine were added, and the mixture was further reacted for 1 hour. To the reaction mixture were added 2.61 g. (0.0125 mole) of Z-Gly.OH having an amino group protected with Z and 10 ml. of pyridine, and the mixture was reacted under reflux for 1 hour. After completion of the reaction, pyridine was removed by distillation under reduced pressure, and the residue was extracted with 100 ml. of ethyl acetate. The ethyl acetate layer was washed with 2 N--HCl, a saturated aqueous NaHCO3 solution and water in this order and then dried over anhydroush Na2SO4, and thereafter ethyl acetate was removed by distillation under reduced pressure. The resulting residue was allowed to stand to form a solid, which was then recrystallized from ethanol to obtain N-benzyloxycarbony glycine p-nitrophenyl ester (hereinafter represented by ##STR9## in a yield of 75% (3.0 g.).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[P:5]([O:12]CC)([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]>C(Cl)(Cl)Cl>[CH2:1]([P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: CCOP(OCC)OCC
Reactant: C=CCBr
Solvent: ClC(Cl)Cl
Product: C=CCP(=O)(OCC)OCC
Temperature: 25 °C

Procedure:
Allyl bromide (3.6 g, 30.09 mmol) and triethyl phosphite (1 g, 6 mmol) were dissolved and reacted in chloroform (30 mL). Then, the resulting reaction solution was refluxed for 12 hours, cooled to room temperature and filtered through a glass filter. Chloroform was completely removed from the solution under vacuum to thereby give an oily compound as the title compound. The 1H NMR and 13CNMR results of the compound thus obtained are given as follows.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C[O:17][CH:18](O)[C:19]([F:22])([F:21])[F:20]>>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:18]([OH:17])[C:19]([F:22])([F:21])[F:20]
Reactant: COC(O)C(F)(F)F
Reactant: Cn1ccc(=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A mixture of 3-hydroxy-1-methyl-1H-pyridin-4-one (7.60 g, 60.7 mmol) and K2CO3 (0.84 g, 6.07 mmol) in trifluoroacetaldehyde methyl hemiacetal (26 mL) was sealed in a parallel reactor and stirred for overnight at 120° C. The reaction mixture was evaporated to dryness, and the residue was purified by flash column chromatography on silica gel using a mixture of isopropyl alcohol and a conc. NH4OH solution (80/20, v/v) as eluant. Pure fractions were combined together and evaporated to give the title compound as a white solid (2.32 g, 17% yield). HPLC purity (peak area percent) of this compound is 99% at λ=254 nm. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.59 (d, J=7.2 Hz, 1H), 6.20 (d, J=7.4 Hz, 1H), 5.80 (q, J=8.5 Hz, 1H) and 3.83 (s, 3H); MS-ESI (m/z): 223.7 [M+1]+, 206, 158. Other fractions were combined to give a second crop of the product (8.26 g, 61% yield). HPLC purity (peak area percent) of this compound is 98% at λ=254 nm. HPLC method: Column: Waters Symmetry C18; 5 μm, 3.9×150 mm; Mobile phase: A=the aqueous phase: 0.035% HClO4 pH 2.5; B=the organic phase: CH3CN; gradient: % B: 0 min—10%, 10 min—90%, 12 min—90%, 15 min—10%; flow rate: 1 mL/min; wavelength: 220, 254, 280 nm.