Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(N)sc2ccc(C)cc12
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CS(C)=O
Product: COC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccc(C)cc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using methyl 2-amino-5-methylbenzo[b]thiophene-3-carboxylate (3.11 g), 2,4-difluoronitrobenzene (1.54 ml) and dimethyl sulfoxide (30 ml), methyl 2-(5-fluoro-2-nitroanilino)-5-methylbenzo[b]thiophene-3-carboxylate was obtained.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13](Cl)[N:12]=1.C(N(CC)CC)C>C(#N)C>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: NCCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
Phenethylamine (7.0 g, 58.4 mmol) was added to a stirred solution of 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (14.5 g, 53.1 mmol) (preparation 5) and triethylamine (21 g, 212.5 mmol) in acetonitrile (200 ml). The reaction mixture was stirred for 3 hr at room temperature and then more phenethylamine (1 g, 8.3 mmol) was added. The reaction mixture was stirred for a further 1 hr and then the solvent was removed under reduced pressure to give a residue which was partitioned between diethyl ether (500 ml) and water (250 ml). The diethyl ether layer was washed with more water (300 ml). The solvent was removed from the organic phase under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with diethyl ether to give the title compound (17.9 g) as a white solid.
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH2:10]([CH2:12][NH2:13])[OH:11].C(OC(=O)C)C>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:5]([CH:4]=[C:3]1[NH:13][CH2:12][CH2:10][O:11]1)([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C=C1NCCO1
Temperature: 25 °C
Yield: 259.8 %

Procedure:
p-Toluene sulfonic acid (0.5 g) was added to a boiling solution of 1,1-bis-methylsulfanyl-2-nitro-ethene (I-1b: 20 g, 12.13 mol) in ethanol (200 mL). This was followed by the addition of ethanolamine (7.4 g, 12.13 mmol) and the resulting mixture was heated to reflux for 12 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated, 300 mL of water added and resultant filtered. The filtrate was further concentrated and was followed by the addition of acetone. The reaction mixture was refluxed for 1 hour, cooled to room temperature, and filtered. The acetone layer was concentrated to afford 4.1 g of the crude product which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Sn](C)(C)[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[N:43][CH:44]=1>CN1C(=O)CCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:45][C:42]1[CH:41]=[CH:40][C:39]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:44][N:43]=1
Reactant: Cc1ccc([Sn](C)(C)C)cn1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)CCC2=O)cn1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 21.4 %

Procedure:
To a degassed r.t. solution of 2-bromo-3-(4-(methylsulfonyl)-phenyl)-2-cyclopenten-1-one (0.315 g, 1.0 mmol), Pd2 (dba)3 (0.018 g, 0.02 mmol), and AsPh3 (0.049 g, 0.16 mmol) in NMP (2.5 mL) was added a degassed NMP solution (2.5 mL) of 5-trimethylstannanyl-2-methylpyridine (~2.0 mmol). The resulting mixture was heated to 60° C. for 16 hours, then to 100° C. for a further 3.5 h. The mixture was then cooled to r.t., diluted with EtOAc, washed 2 times with 10% NH4OH and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (100% EtOAc/hexanes) to provide 0.070 g of the title compound as a rigid foam.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:16]=[C:15]([C:17]3[C:26]4[C:21](=[C:22](B5OC(C)(C)C(C)(C)O5)[CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][N:18]=3)[CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH2:4][CH2:3]1.[NH2:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41](Br)[CH:42]=1.C(=O)([O-])[O-:45].[Na+].[Na+]>COCCOC.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>[NH2:36][C:37]1[CH:42]=[C:41]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH:20]=[CH:19][N:18]=[C:17]3[C:15]2[CH:14]=[CH:13][C:10]([C:11]([NH2:12])=[O:45])=[C:9]([NH:8][CH:5]3[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]3)[CH:16]=2)[CH:40]=[N:39][CH:38]=1
Reactant: CC1(C)OB(c2cccc3c(-c4ccc(C#N)c(NC5CCC(O)CC5)c4)nccc23)OC1(C)C
Reactant: O=C([O-])[O-]
Reactant: Nc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)c1ccc(-c2nccc3c(-c4cncc(N)c4)cccc23)cc1NC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Pd(PPh3)4 (0.013 g) was added to a solution of compound (2b) (0.102 g), 3-amino-5-bromopyridine (0.042 g), and an aqueous sodium carbonate solution (2 M, 1.5 mL) in ethylene glycol dimethyl ether (3 mL) in a nitrogen atmosphere, and the mixture was stirred at 85° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off. An aqueous sodium hydroxide solution (4 M, 0.093 mL) and a 300 aqueous hydrogen peroxide solution (0.045 mL) were added to a solution of the obtained residue in DMSO (3 mL) and ethanol (1.5 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the deposit was collected by filtration, then washed with water and ether by sprinkling, and then dried under reduced pressure to obtain compound (2) (0.045 g, yield based on 2 steps: 45%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.N>C1(C)C=CC=CC=1.O>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[CH3:7]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COC1CCCCO1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
100.00 kg (960.52 mol) ethyl glycolate (A) were dissolved in 180.0 L toluene and 365.22 g (1.92 mol) 4-toluenesulphonic acid monohydrate were added. At 20° C. a solution of 80.80 kg (960.52 mol) 3,4-dihydro-2H-pyran was added dropwise to the reaction mixture obtained and then the mixture was washed with 20.0 L toluene. The reaction mixture was stirred for 1 hour at 20° C. and after the reaction was complete it was combined with 100.0 L water and 6.53 kg (96.05 mol) ammonia solution (25%). After phase separation the organic phase was washed with 100.0 L water and then the solvent was distilled off completely in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[C:14]1(C)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[CH2:27](N(CC)CC)C>>[C:18]1([CH3:27])[CH:19]=[CH:14][C:15]([N:20]2[CH2:21][CH2:22][N:23]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:24][CH2:25]2)=[CH:16][CH:17]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Product: Cc1ccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with p-tolylpiperazine dihydrochloride in the presence of triethylamine to give 1-(p-tolyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]1[CH2:14][C@H:13]([S:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][N:11]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])(=[O:3])[NH2:2].SCCO>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C@@H:10]1[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=1)=[O:36])(=[O:3])[NH2:2]
Reactant: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: OCCS
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To a solution of (2S,4S)-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (1.76 g) in trifluoroacetic acid (10 ml) was added 2-mercaptoethanol (0.38 ml) under ice-cooling and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in toluene (10 ml) and the solution was evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (50 ml), washed successively with saturated aqueous sodium hydrogen carbonate (20 ml) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (0.58 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=2)[C:7]([OH:9])=O)[CH2:3][CH2:2]1.FC1C=C(C=C(C(F)(F)F)C=1)[C:21]([N:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[O:38][CH3:39])C)=O>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=2)[C:7]([N:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:30]=2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[O:38][CH3:39])[CH3:21])=[O:9])[CH2:2][CH2:3]1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C2CC2)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C2CC2)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 3-cyclopropyl-5-methanesulfonyl-benzoic acid (119 mg, 495 μmol) and 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) after a reaction time of 19.5 hours. The compound was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Off-white solid (0.082 g; 36%). MS (ESI): m/z=455.14 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:19])[C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:17])[CH2:14][O:15][CH3:16])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH3:38][O:37][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][C:21]=1[NH:20][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:19])[C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:17])[CH2:14][O:15][CH3:16])[C:25]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:26]
Reactant: COCC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: CO
Solvent: O
Product: COCC(C)N1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Temperature: 100 °C

Procedure:
10-chloro-2-(1-methoxypropan-2-yl)-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 112 60 mg, 0.21 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 56 mg, 0.21 mmol), and p-toluenesulphonic acid monohydrate (100 mg, 0.53 mmol) were combined in 4-Methyl-2-pentanol (2 mL) and heated at 100° C. for 16 hrs. The reaction mixture was cooled to room temperature and dissolved in Methanol. The resultant solution was added to a 5 g SCX-3 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and crude product eluted with 2M ammonia in MeOH and solvents evaporated. The resultant residue was dissolved in DCM and purified on silica eluting with a gradient of 5-15% MeOH/DCM. Product containing fractions were combined and evaporated to a yellow gum which was purified by base modified reverse phase HPLC to give the title compound as a beige solid. (35 mg, 32%)
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([O-:3])=O.C1(N=C=[O:23])C=CC=CC=1.C(N(CC)CC)C.[CH:31]1[CH:36]=CC=C[CH:32]=1>>[CH2:5]([C:4]1[CH:32]=[C:31]([CH2:36][OH:23])[O:3][N:1]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCCCC[N+](=O)[O-]
Reactant: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCc1cc(CO)on1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a solution of 1-nitroundecane (38.0 g) and 0-trimethylsilylpropynol (24.1 g) in dry benzene (30) ml) was added dropwise a solution of freshly distilled phenylisocyanate (44.9 g) and triethylamine (22.4 g) in dry benzene (50 ml) at 40° C., with stirring. The reaction mixture was heated at 60° C. for 3 hrs, cooled, and filtered. To the filtrate was added 1.0M tetrabutylammoniun fluoride (40 ml). After 30 mins, the solution was evaporated, and the residue was flash chromatographed (silica gel, 1% methanol-dichloromethane) to give 15.5 g (34%)of product, mp 55°-56° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]12[O:19][CH:15]([CH2:16][NH:17][CH2:18]1)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2.C(N(C(C)C)CC)(C)C>C(O)C>[CH3:7][N:6]1[C:2]([N:17]2[CH2:18][CH:11]3[O:19][CH:15]([CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]3)[CH2:16]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Yield: 65 %

Procedure:
To a microwave reaction vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (141 mg, 0.88 mmol), tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (200 mg, 0.88 mmol). Ethanol (8 mL) and diisopropylethylamine (0.92 mL, 5.25 mmol) were added and the mixture was irradiated with a microwave for 60 min at 130° C. The mixture was cooled, concentrated and purified via flash chromatography, ethyl acetate/heptane 0% to 100% to afford yellow oil tert-butyl 7-(2-methyl-4-nitro-pyrazol-3-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (202 mg, 65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:41][CH:42]([C:48]#[N:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1COCC1>[C:48]([CH:42]([NH:41][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])#[N:49]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C#N)NC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
To a solution of picolinic acid (1.23 g, 10 mmol), EDC.HCl (1.91 g, 10 mmol) and HOBT (1.35 g, 10 mmol) in THF (80 mL) was added DIPEA (3.6 g, 30 mmol) at ambient temperature. The reaction mixture was maintained at the same temperature for 1 hr at which time a solution of ethyl 2-amino-2-cyanoacetate (1.28 g, 10 mmol) in THF (5 mL) was added. The reaction mixture was stirred at ambient temperature for additional 6 hr. It was then concentrated, and the residue was purified by silica gel column chromatography (5:1 PE/EtOAc) to give ethyl 2-cyano-2-(picolinamido)acetate (0.7 g, 30%) as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6][C:7]([CH:9]=[C:10]([N:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O.[O-]CC.[Na+].C(O)(=O)C>C(O)C.C(OCC)(=O)C>[CH3:24][N:17]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:7]([CH2:6][O:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([CH3:1])[CH:3]=2)[CH:9]=[C:10]1[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CN(C)C(=CC(=O)COc1cccc(C)c1)COC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(COc2cccc(C)c2)cc(COC(C)(C)C)n1C
Temperature: 25 °C

Procedure:
To a solution of 1-(3-methylphenoxyacetyl)-2-(N-ethoxycarbonylmethyl-methylamino)-3-t-butoxy-1-propene (40 g, 0.1 mol) in absolute ethanol (250 ml) is added sodium ethoxide (1.0 g, 0.015 mol) under N2. The reaction is stirred at room temperature and monitored by TLC until all starting material has disappeared. Then acetic acid (0.9 g, 0.015 mole) is added and the mixture taken to dryness in vacuo. The residue is dissolved in ethyl acetate (200 ml) and washed with water (100 ml), then saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent is removed and the crude product is purified by preparative HPLC to afford pure ethyl 1-methyl-2-(t-butoxymethyl)-4-(3-methylphenoxymethyl)pyrrole-5-carboxylate
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1.[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28]>>[Cl:23][CH2:24][CH2:25][NH:26][C:27]([N:22]([CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:28]
Reactant: O=C=NCCCl
Reactant: NCCCN1CCOCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C(NCCCl)N(CCCN1CCOCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 42.5 %

Procedure:
3.6 g of D-galactose, 5.7 g of (3-morpholinopropyl)amine and 3.0 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 23-(1). 3.5 g of 1-(2-chloroethyl)-3-(3-morpholinopropyl)-3-(D-galactopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][CH2:35][C:36]1[N:40]([C:41]2[S:42][C:43]([CH2:55][CH3:56])=[CH:44][C:45]=2[C:46](=[O:54])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])[C:39]([CH3:57])=[N:38][N:37]=1.C(N(CC)CC)C.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)C=O>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:46]([C:45]1[CH:44]=[C:43]([CH2:55][CH3:56])[S:42][C:41]=1[N:40]1[C:39]([CH3:57])=[N:38][N:37]=[C:36]1[CH2:35][NH:34][C:1](=[O:11])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:54]
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2)s1
Reaction time: 24 h
Yield: 66.3 %

Procedure:
trans-Cinnamic acid (1.48 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.42 g) and triethylamine (5.6 ml) were dissolved in dimethylformamide (50 ml). 1-Benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 4.42 g) was added, and the mixture was stirred for one day. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated to give 5.05 g of crude crystals. The crystals were recrystallized from ethyl acetate to give 3.25 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-phenylacrylamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].Cl>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2cccc(NCCN)c2)c1
Reaction time: 16 h
Yield: 22 %

Procedure:
To methyl-3′-[(2-[[(tert-butoxy)carbonyl]amino]ethyl)amino]-[1,1′-biphenyl]-3-carboxylate (730 mg) was added 4 N HCl in dioxane (20 mL) and the mixture was stirred under nitrogen for 16 h. The white mixture was diluted with ether, and the dihydrochloride salt of the title compound was collected as a white solid (566 mg) by suction filtration. A portion of this material (128 mg) was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound (117 mg) as a colorless oil. Electrospray MS (positive ion): (M+H) 272
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][CH:3]1[CH2:12][C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:22]=O.ClCCCl.C(O)C>C(O)C.C(O)(=O)C>[O:1]=[C:2]1[CH:3]([CH2:12][C:13]([NH:15]/[N:16]=[CH:22]/[C:21]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=2)=[O:14])[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7]1
Reactant: NNC(=O)CC1Sc2ccccc2NC1=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CCO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(/C=N/NC(=O)CC2Sc3ccccc3NC2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a round-bottom glass flask equipped with a magnetic stir bar (3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid hydrazide (1 eq. 0.063 mmol; 15 mg) was dissolved in ethanol (3 mL) at room temperature. To this well stirred solution, acetic acid (˜3 drops) and 3,4,5-trimethoxy-benzaldehyde solution (0.063 mmol; 12.4 mg dissolved in 0.5 mL of ethanol) were added, and the reaction mixture was stirred for another 5 hours at ambient temperature and monitored by TLC (typically with 1,2-dichloroethane-ethanol 5:1). The mixture was then concentrated under vacuum using a rotary evaporator. The crude product was diluted with hexanes and triturated. The precipitated solid product was transferred to a glass fiber funnel, the supernatant was removed by vacuum filtration and the solid was washed thoroughly with n-hexane twice to yield: 16 mg (61%) of 1-1.