Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23]>O>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH:23][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CN(C)CCCN
Solvent: O
Product: CN(C)CCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (22.4 g) in water (24 ml), 3-dimethylaminopropylamine (120 ml) was added, while cooling. Then the reaction mixture was heated to 100°C and kept at this temperature for 2 hours. After cooling and evaporating in vacuo to dryness, the residue was dissolved in water (80 ml) and adjusted to a pH of 7.5 by addition of 4N hydrochloric acid. The precipitated 4-(3-dimethylaminopropylamino)-3-nitro-5-sulphamyl-benzoic acid was collected by suction and recrystallized from water. The melting point was 262°C (decomp.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](O)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][CH2:27][OH:28])=[CH:24][CH:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:21]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:28][CH2:27][CH2:26][C:25]3[C:20]([CH3:19])=[N:21][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=4)=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCOc1ccc2c(ccn2CC(=O)OC(C)(C)C)c1

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 5 b]) was reacted with 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine in tetrahydrofuran to yield (5-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][O:28][CH:29]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1ccoc1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccoc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and 3-furanylboronic acid (54 mg, 0.48 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was purified by SCX followed by mass directed autoprep HPLC to afford the title compound (E118). MS (ES+) m/e 442 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12](OCC)=[O:13])[O:9]2)=[CH:4][CH:3]=1.[BH4-].[Li+]>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:12][OH:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCc2ccc(N)cc2O1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(CO)CC2
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of ethyl 7-amino-2-chromancarboxylate (1.26 g, 5.7 mmol) in anhydrous THF is treated dropwise with lithium borohydride (2.0 M in THF, 13.7 mmol), stirred under nitrogen at ambient temperatures for 4 h, quenched with methanol, stirred at ambient temperatures for 1 h, poured into water, extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo to afford the title compound as a nearly colorless oil, 0.9 g (90% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([CH2:16][OH:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([CH:16]=[O:17])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(CO)cnn1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCCc1c(C=O)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
A mixture of (1-benzyl-5-propyl-1H-pyrazol-4-yl)methanol (14.99 g), activated manganese dioxide (30.0 g) and, tetrahydrofuran (300 ml) was stirred at room temperature for 3 days. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-5-propyl-1H-pyrazole-4-carbaldehyde (10.69 g, yield: 72%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].CO.[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:20]1=2)[CH3:18].[BH4-].[Na+]>O>[CH2:17]([N:19]1[C:25](=[O:26])[C:24]([CH3:27])([CH3:28])[C:23](=[O:29])[N:22]([CH3:30])[C:21]2[CH:31]=[C:32]([CH2:35][NH:1][CH2:2][CH2:3][N:4]3[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:14])[CH:33]=[CH:34][C:20]1=2)[CH3:18]
Reactant: NCCn1ccc2ccccc2c1=O
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCn3ccc4ccccc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
2-(2-Aminoethyl)-2H-isoquinolin-1-one (1.0 g) was added to a methanol solution (15 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (1.46 g). The mixture was stirred for 0.5 hours at room temperature. Sodium borohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→8:2). The purified product was condensed under reduced pressure to give the title compound (1.92 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].CN1CCOCC1.[CH2:16]([O:23][C:24]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(O)(=O)C>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH:6][C:35](=[O:36])[C@H:27]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH:26][C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
First benzyloxycarbonyl-L-phenylalanyl-D-alanine methyl ester was prepared, as follows. A solution of 0.56 g of D-alanine methyl ester hydrochloride in 6 ml tetrahydrofuran was cooled to 0° C. and then treated with 0.53 ml of N-methylmorpholine. After 15 min of stirring, 1.20 g of benzyloxycarbonyl-L-phenylalanine and 1.08 g of 1-hydroxybenzotriazole were added. A cold solution of 0.99 g of N, N'-dicyclohexylcarbodiimide in 2 ml tetrahydrofuran was then added and the mixture stirred for 1 hour at 0° C., then overnight at room temperature. After adding 0.3 ml of glacial acetic acid, the mixture was stirred 5 min., filtered, and the filtrate concentrated in vacuo to dryness. The residue was dissolved in CHCl3, washed 3 times with 5% aqueous NaHCO3, dried over anhydrous Na2SO4, and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (silica 60 g) using CHCl3 followed by CHCl3 -acetone 10:1 as eluant. Appropriate fractions were pooled and the solvent removed in vacuo to obtain 0.74 g of white solid, m.p. 134-136 C. TLC on silica gel using an eluant of 10 acetone gave Rf =0.37.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:33][S:34]([CH2:37][C:38]#[N:39])(=[O:36])=[O:35].C(O)(=O)C.N1CCCCC1>C(O)C>[CH3:33][S:34]([C:37](=[CH:21][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:10]3=[N:11][CH:12]=2)=[CH:24][CH:23]=1)[C:38]#[N:39])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)CC#N
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)S(C)(=O)=O)cc3)nc12
Yield: 64 %

Procedure:
To a 10 ml seal tube, 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.1 g, 0.00022 mol) and 2-(methylsulfonyl)acetonitrile (0.105 g, 0.00088 mol) were taken in ethanol (5 ml). Piperidine acetate (3.3 M solution in water) (1.0 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed for 24 hr. After completion of the reaction, ethanol was distilled out to obtain crude product. The crude product was purified by column chromatography using 30% ethyl acetate in hexanes to yield 0.078 g of 2-(methylsulfonyl)-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile which was converted to the title compound as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O-]S([O-])(=O)=O.[Na+].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[C:19]([N+:25]([O-])=O)[CH:18]=1.[In].II>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:21]2[N:5]([C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=3)[N:25]=[C:19]3[C:20]=2[CH:23]=[CH:24][C:17]([F:16])=[CH:18]3)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: Nc1cccc(Cl)c1
Agent: II
Agent: O=S(=O)([O-])[O-]
Agent: [In]
Solvent: C1CCOC1
Product: Fc1ccc2c(Nc3cccc(Cl)c3)n(-c3cccc(Cl)c3)nc2c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
3-Chloroaniline (12.4 ml, 118 mmol; [108-42-9]) and Na2SO4 (3.36 g, 24 mmol) were added to a solution of 4-fluoro-2-nitro-benzaldehyde (1 g, 6 mmol; [2923-96-8]) in THF (12 ml) under an argon atmosphere. The suspension was stirred at 50° C. for 16 h. Na2SO4 was removed, indium (2.04 g, 18 mmol) and iodine (1.2 g, 5 mmol) were added and the reaction mixture was stirred at 50° C. for 24 h. The mixture was filtered over celite and the filtrate was poured onto 1 M aqueous HCl solution/iPrOAc 1/1. The aqueous layer was extracted one more time with iPrOAc and the combined extracts were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by crystallization (CH2Cl2) to give the title compound (672 mg, 1.8 mmol; 31%) as white powder. MS: m/e=372.0 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[CH:21])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+:24]>CO>[Na+:24].[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][C:3]([O-:22])=[O:2])[CH2:11][CH2:10]2)=[CH:13][CH:14]=1)[C:20]#[CH:21]
Reactant: C#CCOc1ccc(N2CCN(CCC(=O)OC)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1ccc(N2CCN(CCC(=O)[O-])CC2)cc1
Temperature: 65 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
The compound from step 2 (175 mg, 0.55 mmol) was dissolved in methanol (4 mL) followed by addition of 1N NaOH aqueous solution (0.55 ml, 0.55 mmol). The reaction solution was stirred at 60-70° C. for 4 h and then evaporated under vacuum to dryness. The residue was stirred with ethyl acetate (4 mL) and the solid was collected by filtration and washed with ethyl acetate to give the title product as an off-white solid (75 mg, 42%); MS; m/z 289 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([Cl:34])[CH:28]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13])=[C:29]([Cl:34])[CH:28]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1Cl
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Oxalyl chloride (0.029 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.047 g) in dichloromethane (3 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 30 minutes and was then added to a solution of 4-(4-bromophenylsulphonyl)-2-chloroaniline (Method 12) (0.104 g) in dichloromethane (3 ml) and stirred a further 1 hour. Water (10 ml) was added and the mixture was extracted with dichloromethane (3×20 ml). The organic extracts were combined, washed with brine then dried. Volatile material was removed by evaporation and the residue was purified by flash chromatography on silica gel eluting with 1% methanol/dichloromethane to give the title compound (0.049 g) as a foam. NMR (CDCl3): 1.78 (s, 3H), 7.65 (d, 2H), 7.8 (m, 3H), 8.0 (s, 1H), 8.6 (d, 2H), 9.3 (s, 1H);MS: 485 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH2:28][CH2:29][C:30]([NH2:32])=[O:31]>>[C:30]([CH2:29][NH:28][C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26])(=[O:31])[NH2:32]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: NCC(N)=O
Product: NC(=O)CNC(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with glycinamide at 22° C. to give the title compound as a colorless gum. MS: 432.3 ([M−H]−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])=[O:12])=[CH:3][CH:2]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][C:19]([C:18]1[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=1)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]1[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=1[NH:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[O:20]
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1

Procedure:
Prepared by a similar procedure as described for preparation of Example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see Example 403) and 2-dimethylaminoethylamine. 13C-NMR (DMSO-d6) δ 165.8, 149.5, 148.9, 148.2, 136.1, 134.6, 132.4, 131.4, 128.2, 128.0, 127.7, 126.8, 121.9, 114.8, 113.3, 111.4, 76.5, 58.1, 45.2, 44.8, 37.3.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:6][CH2:5][CH:3]2[CH2:4][O:1][CH2:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: OCC1COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of oxetan-3-yl-methanol (300 mg, 3.41 mmol, CAS RN 6246-06-6) in CH2Cl2 (3 mL) was added triethylamine (517 mg, 712 μl, 5.11 mmol), DMAP (41.6 mg, 341 μmol) and p-toluenesulfonyl chloride (779 mg, 4.09 mmol) at 0° C. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured on 30 mL 1M aqueous HCl and 30 mL CH2Cl2 and the layers were separated. The aqueous layer was extracted a second time with 30 mL CH2Cl2. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless liquid (595 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C(O)(=O)C>[C:2]1([N:1]2[C:11](=[O:12])[C:10]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]3[C:8]2=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1

Procedure:
The reaction of aniline 3.8 g (0.041 mol) with phthalic anhydride 4.0 g (0.041) mol in 100 ml of refluxing glacial acetic acid for 3 hours, followed by precipitation from water, filtration and vacuum drying at 120° C., afforded an 8.2 g (91%) yield of product, m.p. 205°-9° C. (from ethanol). Lit. reports m.p. 210° C. ("Dict. Org. Cpds", 5, 2740(1965), Oxford Univ. Press, NY). Anal. Calcd. for C14H9NO2 : C, 75.33; H, 4.06. Found: C, 75.10; H, 4.17%. Ir(KBr): 1765, 1700, and 1375 cm-1 (imide).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C@H:12]([NH:14][CH2:15][C@@H:16]([O:23][Si](C(C)(C)C)(C)C)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])=[CH:8][CH:7]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C@H:12]([NH:14][CH2:15][C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:23])[CH3:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@@H](O)c2ccccc2)cc1
Yield: 75.7 %

Procedure:
Following a procedure similar to that described in Example 27, but using 880 mg of N-[2-(4-methoxycarbonylmethylphenoxy)-1(R)-methylethyl]-2(S)-t-butyldimethylsilyloxy-2-phenylethanamine (prepared as described in Preparation 32), 20 ml of tetrahydrofuran and 1.5 g of tetrabutylammonium fluoride, 0.5 g of the title compound was obtained as crystals, melting at 90°-91° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:12][O:13][CH2:14][C:15]3[S:19][C:18]([C:20]([OH:22])=O)=[CH:17][CH:16]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C.C1(N)C=CC=CC=1N>ClCCl>[NH2:24][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:20]([C:18]1[S:19][C:15]([CH2:14][O:13][N:12]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: O=C(O)c1ccc(CON=Cc2ccc3c(c2)OCCO3)s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(CON=Cc2ccc3c(c2)OCCO3)s1
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A solution of 100 mg (0.31 mmol) 5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyleneaminooxymethyl)-thiophene-2-carboxylic acid, 65 mg (0.47 mmol) 1-hydroxybenzotriazol, 92 mg (0.47 mmol) N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide and 65 μl (0.47 mmol) triethylamine in 3 ml dichloromethane was stirred for 15 minutes. After addition of 68 mg (0.63 mmol) phenylenediamine the reaction mixture was stirred overnight. The solvent was evaporated and the residue was subjected to preparative HPLC to yield 88 mg (0.21 mmol) 5-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyleneaminooxymethyl)-thiophene-2-carboxylic acid (2-amino-phenyl)-amide (17); exact MW [M+H] calc'd: 410.12; MW found [M+H]: 410.2. 1H-NMR (400 MHz, (CH3)2SO): δ=9.67 (s, 1H), 8.18 (s, 1H), 7.85 (m, 1H), 7.20 (m, 1H), 7.14–7.09 (m, 3H), 6.97 (m, 1H), 6.91 (m, 1H), 6.77 (m, 1H), 6.58 (m, 1H), 5.29 (s, 2H), 4.90 (s, 2H), 4.26 (m, 4H)
Reaction SMILES: CC1(C)OC(=O)[CH:5]([CH2:9][C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:4](=[O:30])O1>C1(C)C=CC=CC=1>[O:30]=[C:4]1[CH2:5][CH2:9][C@H:10]([CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=2)[N:22]1[C:23]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)nc1)CC1C(=O)OC(C)(C)OC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)nc1
Yield: 67.4 %

Procedure:
(R)-tert-Butyl 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)propan-2-ylcarbamate (2.5 g, 5.6 mmol) in 100 mL toluene was heated at 105° C. for 8 hours. After removing the solvent, the residue was purified by chromatography on silica gel (20-40% EtOAc in hexane) to provide the product (1.3 g, 67%) as a white solid. LCMS (API-ES) m/z (%): 345.0 (100%, M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1I)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1)#[CH:19]>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[C:19]#[C:18][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cccc(S(=O)(=O)CCC)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(Br)cc1I
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(Br)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-bromo-2-iodo-phenoxy)-acetic acid tert-butyl ester (Intermediate 190) and 1-ethynyl-3-(propane-1-sulfonyl)-benzene (Intermediate 42), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.