Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2]([CH3:19])[CH2:3][N:4]1[C:18]2[C:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[N:5]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>O1CCCC1>[N:36]([C@@H:2]([CH3:19])[CH2:3][N:4]1[C:18]2[C:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[N:5]1)=[N+:37]=[N-:38]
Reactant: C[C@@H](O)Cn1ncc2ccc3oc(C(N)=O)nc3c21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)nc3c21)N=[N+]=[N-]
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 18.3 %

Procedure:
To a suspension of the product from Step D (0.90 g, 3.45 mmol) in tetrahydrofuran (20 mL) was added triethylamine (1.93 mL, 13.9 mmol); this mixture was cooled (ice bath), methane sulfonic anhydride (1.20 g, 6.92 mmol) was added, and the mixture was stirred for 20 minutes. Sodium azide (2.25 g, 34.6 mmol) was added and the mixture was evaporated to a residue which dissolved in dimethyl sulfoxide (20 mL) and heated at 90° C. for 2.5 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with water (100 mL), dried (magnesium sulfate), filtered, and evaporated to solid (0.97 g). This residue was purified by chromatography (silica gel, ethyl acetate gradient) and recrystallized from methanol and ethyl acetate to give a colorless solid (0.18 g, 18%): mp 162–164° C.; LC/MS m/z 286.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C(C)=C)[CH2:2][CH2:3]C.Br[C:18]1[CH:25]=[C:22]([CH:23]=[O:24])[C:21]([O:26][CH3:27])=[CH:20][CH:19]=1.CCOCC.[F-].[K+]>C1(C)C=CC=CC=1>[C:2]([C:18]1[CH:25]=[C:22]([CH:23]=[O:24])[C:21]([O:26][CH3:27])=[CH:20][CH:19]=1)([CH3:3])=[CH2:1]
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(Br)cc1C=O
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C)c1ccc(OC)c(C=O)c1
Reaction time: 3 h

Procedure:
Tri-n-butyl-isopropenyltin (12.1 g, 36.6 mmol) dissolved in toluene (10 ml) was added to a mixture of 5-bromo-o-anisaldehyde (6.00 g, 27.9 mmol), tetrakis (triphenylphosphine)palladium (1.21 g, 1.05 mmol), and 2,6-t-butyl4-methylphenol (10 mg) in toluene (50 ml) under nitrogen at room temperature. This mixture was heated at reflux for 7 hr. Ether and aq. KF solution (80 ml) were added to the reaction mixture, and the resulting solution was stirred for 3 hr. Insoluble materials were removed by filtration through Celite. The filtrate was extracted with ether, and the organic phase was washed with 1N-NaHSO4 aq. NaHCO3 and brine. The extracts were dried over Na2SO4, and concentrated by evaporation. The residual oil was purified by chromatography (SiO2, 140 g, 5%-EtOAc/hexane) to afford 5-isopropenyl-o-anis-aldehyde, as a yellow oil (2.49 g, 51%).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[S:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH3:19]>C1COCC1>[NH2:19][C:1]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[S:2]
Reactant: N
Reactant: C1COCCN1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: NC(=S)N1CCOCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
A solution of 3.35 g (18.8 mmol) of thiocarbonyl diimidazole in 100 ml of THF was treated with 0.82 ml (9.4 mmol) of morpholine. After being stirred at ambient temperature for 3.5 h, an additional 0.82 ml portion of morpholine was added, and stirring was continued. After 6 h, the solution was treated with excess concentrated aqueous ammonia, and stirred overnight. The resulting solution was concentrated in vacuo, taken up in chloroform, separated from the aqueous phase, dried over Na2SO4, and concentrated. Purification of the residue by silica gel chromatography using ethyl acetate provided 1.85 g (76%) of the desired compound, Rf 0.17 (10% methanol in chloroform), as a white solid. 1H NMR (CDCl3) δ 3.76 (m, 4 H), 3.83 (m, 4 H), 5.75 (br, 2 H). Mass spectrum: (M+H)+ =147.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42](C=O)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.[CH3:57]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:50][N:51]6[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]6)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(=O)O
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCN(C)CC4)c3)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-4-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added 1-methyl piperazine (22.8 mg, 0.23 mmol), and AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was purified using a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 90% CH3CN in water at a flowrate of 20 mL/min. Fractions containing product were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-({4-methyl-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-1,3-benzenedicarboxamide as a white solid (33 mg, 29%). LC-MS m/z 744 (M+H)+.
Reaction SMILES: [Li].[C:2]1([P:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([Si:23]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH:19][CH:18]=1.[O:33]1CCCC1>>[C:2]1([P:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:17]2[CH:22]=[CH:21][C:20]([Si:23]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)=[O:33])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Agent: [Li]
Product: CCO[Si](OCC)(OCC)c1ccc(P(=O)(c2ccccc2)c2ccccc2)cc1
Yield: 68.1 %

Procedure:
To the lithium diphenylphosphide solution prepared under nitrogen from lithium (0.6246 g, 0.09 g atom) and diphenylphosphinous chloride (9.92 g, 0.045 mol) in 50 ml dry tetrahydrofuran, 14.5 g (0.045 mol) of 4-bromophenyl triethoxysilane dissolved in 50 ml dry tetrahydrofuran is added during one hour. The blood-red solution turns to a light brown color with the appearance of a small amount of white solid. The solution is filtered under nitrogen, diluted with benzene to precipitate remaining lithium bromide, and refiltered. Analysis of the solution by gasliquid chromatography shows a content of unreacted bromosilane of 3.88 grams (0.0122 mol). Distillation in vacuum gives 4-(diphenylphosphinyl)phenyl triethoxysilane (13 grams, 68.1 percent yield), b.p. 164°-167° C/0.1 mm. The H'NMR spectrum is identical to the material prepared from 4-(diphenylphosphinyl)phenyl magnesium bromide and tetraethyl orthosilicate. The efficiency based upon bromosilane consumed is 93.4 percent.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[CH2:9])(=[O:4])=[O:3].[N+](=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[N-]>ClC1C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:17][C:12]1[CH:11]=[C:10]([C:8]2([CH2:7][CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:9][C:20]2([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: C=C(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1(C(=O)OC)CC1(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
In a round-bottomed flask, 3-(3,4-dichlorophenyl)-3-buten-1-yl methanesulfonate (P62, 90.8 g, 308 mmol) was dissolved in chlorobenzene (200 ml) to give a green solution. Rhodium acetate dimer (6.80 g, 15.38 mmol) was added. The suspension was warmed to an internal temperature of +65° C. and dimethyl diazopropanedioate (78 g, 492 mmol, for a reference procedure of preparation see Synthetic Communication 1987, 17 (14), 1709-1716) dissolved in chlorobenzene (150 ml) was added dropwise (during 2.5 hrs), keeping the internal temperature below 65-67° C. At the end of the addition, the mixture was cooled to room temperature. It was diluted with DCM (300 ml) and filtered over a celite pad to separate the catalyst.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:27][C:8]2[C:9](=[O:26])[O:10][C:11]3[C:16]([C:7]=2[CH2:6][CH2:5]1)=[CH:15][CH:14]=[C:13]([C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=1)[CH:12]=3)[CH2:2][CH3:3].[CH2:28](O)[CH3:29].[O-:31]CC.[Na+].O>C1COCC1.[Pd]>[CH2:1]([CH:4]1[CH2:27][CH:8]([C:9]([O:10][CH2:28][CH3:29])=[O:26])[CH:7]([C:16]2[CH:15]=[CH:14][C:13]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)=[CH:12][C:11]=2[OH:31])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CC[O-]
Reactant: CCCC1CCc2c(c(=O)oc3cc(-c4cc(F)c(F)c(F)c4)ccc23)C1
Reactant: CCO
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)cc2O)C(C(=O)OCC)C1

Procedure:
10 g (26.9 mmol) of 8-propyl-3-(3,4,5-trifluorophenyl)-7,8,9,10-tetrahydrobenzo[c]chromen-6-one from Example 1 (1.2.) are dissolved in THF and hydrogenated to cessation in the presence of palladium/active carbon catalyst. The mixture is subsequently filtered, the solvent is removed under reduced pressure, and the residue is dissolved in abs. ethanol and, after addition of 5.5 g (80.7 mmol) of sodium ethoxide, refluxed overnight. After addition of water, the mixture is acidified, the solution is extracted with MTB ether and dried over sodium sulfate. The solvent is removed under reduced pressure, and the crude product is purified by crystallisation, giving ethyl 5-propyl-2-(3′,4′,5′-trifluoro-3-hydroxybiphenyl-4-yl)cyclohexanecarboxylate.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:25][CH2:26][CH2:27][CH2:28]I.O>O1CCCC1.CCOCC>[Cl:25][CH2:26][CH2:27][CH2:28][CH:13]1[C:12](=[O:16])[C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][O:9][C:10]=2[CH2:15][CH2:14]1
Reactant: O=C1CCCc2onc(-c3ccccc3)c21
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In 478 ml anhydrous tetrahydrofuran (THF) was dissolved 10.2 g 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 47.8 ml lithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise. The resulting solution was stirred for 10 minutes at -78° C. and 7.7 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and ether. The layers were separated and the aqueous phase was extracted twice with dichloromethane and twice with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (10% ethyl acetate/hexane) gave 6.2 g of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC([O:24][CH:25]([CH3:27])C)=O.[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[CH:36](O)[CH2:35]2.[S:43]1C=CC=C1CC(O)=O>C1COCC1>[C:25]([S:43][CH:36]1[CH:37]2[CH2:40][CH2:41][N:34]([CH2:39][CH2:38]2)[CH2:35]1)(=[O:24])[CH3:27]
Reactant: OC1CN2CCC1CC2
Reactant: O=C(O)Cc1cccs1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CN2CCC1CC2
Reaction time: 8 h
Yield: 71 %

Procedure:
To a THF (300 mL) solution of triphenyl-phosphine (42 g, 160 mmol, 2 equiv) at 0° C. was added diisopropyl azodicarboxylate (32 mL, 162 mmol) to produce a pale yellow solid. A THF (300 mL) solution of 3-quinuclidinol (10.2 g, 80.2 mmol) and thiolacetic acid was added dropwise to the yellow reaction mixture and stirred overnight. THF was removed in vacuo and the residue was dissolved in ether (500 mL) and extracted with 10% HCl (4×150 mL). The aqueous acidic phase was back extracted with ether/ethyl acetate (75 mL/25 mL) and then neutralized to pH 7 by the addition of sodium bicarbonate cautiously in small portions. The aqueous layer was then basified to pH 9-10 by adding a few drops of 10N NaOH, then extracted with dichlormethane (5×200 mL), dried over anhydrous sodium sulfate and concentrated. Purification by flash column chromatrography using 5% MeOH in chloroform as eluent gave 3-acetylthioquinuclidine (10.5 g, 71%). 1H (300 MHz, CDCl3): δ 3.725-3.63 (m, 1H), 3.427 (dd, 10.23 Hz, 13.7 Hz), 2.9-2.75 (dd, 4H), 2.678 (dd, 5.7 Hz, 14.2 Hz, 1H), 2.326 (S, 3H), 1.9-1.82 (m, 1H), 1.81-1.675 (m, 3H), 1.53-1.4 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.BrC1C=C(CC(=O)C)C=CC=1.[Br:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](=[O:31])[CH3:30])[CH:25]=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([CH:28]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:29]([OH:31])[CH3:30])[CH:25]=[N:26][CH:27]=1
Reactant: CC(=O)Cc1cncc(Br)c1
Reactant: ClCc1ccc(Cl)cc1
Agent: CC(=O)Cc1cccc(Br)c1
Product: CC(O)C(Cc1ccc(Cl)cc1)c1cncc(Br)c1

Procedure:
The title compound was prepared following the procedures described in Reference Example 40, Step B-C, substituting 2-bromomethyl-5-chloropyridine with 4-chlorobenzyl chloride and 3-bromophenylacetone with 5-bromo-3-pyridylacetone (Step A). 1H NMR (500 MHz, CD3OD): δ 8.43 (d, 1H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.17 (d, 2H), 7.07 (d, 2H), 4.04 (m, 1H), 3.16 (dd, 1H), 3.0-2.9 (m, 2H), 1.04 (d, 3H).
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:2].C[C:10]([O-:13])([CH3:12])C.[K+].[CH2:15](Cl)Cl>>[C:3]1([N:1]2[CH2:15][CH2:12][C:10](=[O:13])[O:2]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: O=Nc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: O=C1CCN(c2ccccc2)O1

Procedure:
Experiments were also conducted by reacting the following α,β-unsaturated aldehydes represented by the formula (II) as defined above, all with nitrosobenzene in the presence of the IPrCl catalyst (10-20 mol %), KOtBu and CH2Cl2 (r.t., 1-6 h) forming the corresponding N-phenylisoxazolidin-5-one derivatives in the following yields a (%, determined by 1H NMR), and then treating the N-phenylisoxazolidin-5-one derivatives with MeOH in the presence of an acid catalyst (r.t., 12 h) forming the corresponding β-amino acid ester derivatives in the following yields b (%): i) R1=3-Br-4-OTfPh and R2═H; yield a=83%; yield b=79%. ii) R1=4-CNPh and R2═H; yield a=95%; yield b=40%. iii) R1═C6F5 and R2═H; yield a=85%; yield b=72%. iv) R1=3,5-F2Ph and R2═H; yield a=88%; yield b=78%. v) R1═C4H9 and R2═H; yield a=40%; yield b=30%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[O:13].C(O)(=O)C.C([BH3-])#N>CO.ClCCl>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH2:12][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1)#[N:19].[CH:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[O:13]
Reactant: COC(=O)c1ccc(N)cc1
Agent: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(NCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 4-aminobenzoate (0.2 g, 1.323 mmol) and 4-formylbenzonitrile (0.177 g, 1.350 mmol) in methanol (2 ml) and dichloromethane (4 ml) was treated with acetic acid (0.379 ml, 6.62 mmol) followed by MP-cyanoborohydride (1.151 g, 2.65 mmol) and the reaction was slowly stirred at room temperature. After 16 hours, the mixture was filtered and concentrated and the concentrate was partitioned between 2 N sodium hydroxide and dichloromethane. The organic phase was concentrated to give the title compound with 30% of remaining 4-formylbenzonitrile.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH2:5])=[O:4].[C:6](Cl)(=[O:10])C(Cl)=O.[CH3:12][OH:13]>ClCCCl>[CH3:12][O:13][C:6](=[O:10])[NH:5][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: CO
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)CCl
Solvent: ClCCCl
Product: COC(=O)NC(=O)CCl
Temperature: 0 °C

Procedure:
A suspension of 2-chloroacetamide (122.6 g, 1.31 mol) in 300 ml of 1,2-dichloroethane is cooled to 0° C. and treated with oxalyl chloride (200 g, 1.57 mol). The reaction mixture is heated at reflux for 4 hours. After cooling to 5° C., 68 ml of MeOH is added dropwise while keeping the internal temperature below 15° C. with external cooling. After addition is complete, the product is separated by filtration and washed with CH2Cl2 and Et2O. Recrystallization from CH2Cl2 yields methyl(chloroacetyl)carbamate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=O)OC(C)(C)C)[CH2:19][C@H:18]2[CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:13]1=[O:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:38](F)(F)[C:39](O)=O.[CH2:44](Cl)Cl>>[CH:38]([N:23]([CH3:24])[C@@H:20]1[CH2:21][CH2:22][C@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:13]2=[O:36])[C@H:18]([CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:19]1)([CH3:39])[CH3:44]
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(C)(=O)=O)C1
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
Tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (714 mg) was dissolved in CH2Cl2 (15 mL) prior to the addition of trifluoroacetic acid (7 mL). After 1 h at rt, the reaction was concentrated in vacuo. This residue was dissolved in MeOH (15 mL) and charged with acetone (1.0 mL) and NaOAc (558 mg). The mixture was stirred for 5 min before being charged with NaCNBH3 (461 mg). The reaction was stirred for 2 h and then charged with formaldehyde (0.5 mL of a 37% aq. solution) and NaCNBH3 (461 mg). The mixture was stirred for 1 h, quenched with sat. NaHCO3, and extracted with EtOAc (2×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated to afford the benzyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (1.5 g). MS found: (M+H)+=466.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][O-:26].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([O:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1

Procedure:
To 100 mg of 4-(3-bromo-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 3 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 3 hours, the reaction was diluted with water and the product extracted five times with chloroform. The crude product was purified by flash chromatography with 1% triethyl amine and 10% methanol/chloroform followed by recrystallized from chloroform/ether to give 100 mg of 4-(3-bromo-phenylamino)-6-(2-dimethylamino-ethoxy)-[1,7]naphthyridine-3-carbonitrile as a yellow solid: melting point 138-139° C.; mass spectrum (m/e): M+H 411.9, 413.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:18][CH:17]([CH2:19][OH:20])[CH2:16][C@H:15]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][N:28]([CH3:33])[CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:12])=[CH:5]2.[N:34]1[CH:39]=CC=CC=1.ClC(OC1C=CC=CC=1)=[O:42].N>O1CCCC1.CO>[C:39]([O:20][CH2:19][CH:17]1[CH2:18][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@H:15]([NH:21][C:22]([C:24]2[S:25][C:26]3[CH2:27][N:28]([CH3:33])[CH2:29][CH2:30][C:31]=3[N:32]=2)=[O:23])[CH2:16]1)(=[O:42])[NH2:34]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CC(CO)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: c1ccncc1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCc2nc(C(=O)N[C@@H]3CC(COC(N)=O)C[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1R*,2R*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-hydroxymethyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine (Stereoisomer A) (200 mg) was suspended in tetrahydrofuran (80 ml), and pyridine (100 μl) was added, and phenyl chloroformate (156 μl) was then added to stir the mixture at room temperature for 10 minutes. A saturated methanol solution (10 ml) of ammonia was added to the reaction mixture, and the mixture was left to stand overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 1:9 mixed solvent (100 ml) of methanol and dichloromethane and a 1N aqueous solution (50 ml) of sodium hydroxide were added to the residue to conduct liquid separation. The resultant organic layer was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=10:1). The thus-obtained colorless amorphous solid was suspended in 1N hydrochloric acid (1 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (151 mg) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H][H].Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([F:12])([F:13])[F:3])=[CH:10][CH:9]=1)[CH3:21]
Reactant: CCOC(CBr)OCC
Reactant: [H][H]
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(C(F)(F)F)cc1)OCC
Temperature: 120 °C
Yield: 13.3 %

Procedure:
To a suspension of sodium hydride (12.0 g, 500.00 mmol) in anhydrous DMF (500 mL) was added 4-(trifluoromethyl)phenol (35.0 g, 215.90 mmol) at 0° C. After hydrogen evolution had ceased, 2-bromo-1,1-diethoxyethane (55.0 g, 279.09 mmol) was added. The reaction was heated at 120° C. overnight. The mixture was poured into ice-water (2 L), extracted with ethyl acetate (3×150 mL), washed with 1N sodium hydroxide (3×100 mL) and brine (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 1-(2,2-diethoxyethoxy)-4-(trifluoromethyl)benzene as oil (8.0 g, 13%).