Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C([BH3-])#N.[Na+].C([OH:40])C>>[C:19]([O:18][C:16]([C@@H:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:17])(=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCO
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of L-alanyl-L-proline (167 mg) and benzyl 2-oxo-4-phenylbutyrate (1.20 g) in 5 ml of ethanol is stirred at room temperature with 3 g of powdered molecular sieves, type 4A. Sodium cyanoborohydride (75 mg) is then added in portions over the course of three hours. The product is purified by absorption on strong cation exchange resin and elution with 2% pyridine in water. After passage through a gel filtration (LH-20) column 220 mg of N-(1-benzyloxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline is obtained as a mixture of isomers. Thin layer chromatography on silica gel eluted with 1 EtOAc, 1 n-butanol, 1 H2O, 1 HOAc shows one main spot, Rf 0.71. Isomers are separated using reverse phase HPLC to yield N-(1(S)-benzoyloxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH2:12].N1C=CC=CC=1.[CH:20]([O:23][C:24](Cl)=[O:25])([CH3:22])[CH3:21]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[O:25]
Reactant: COC(=O)c1cc(Br)c(Cl)cc1N
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)c(Cl)cc1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 2-Amino-5-bromo-4-chloro-benzoic acid methyl ester (2.08 g, 7.86 mmol) and pyridine (1.91 ml, 23.6 mmol) in dichloromethane (75.0 ml) was added 1.00N isopropylchloroformate in toluene dropwise. The mixture was stirred for 16 hours at room temperature. The mixture washed with 0.500N HCl(aq) (100 ml), and brine (3×100 ml), then dried (Na2SO4) and concentrated to an oil. Purification by silica gel chromatography (gradient eluent, 0-10% ethyl acetate in hexane) provided 5-Bromo-4-chloro-2-isopropoxycarbonylamino-benzoic acid methyl ester (2.53 g, 92%) as a white crystalline material. MS (ES+): 350, 352 (M+H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].O[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
0.6 g of N,N'-dicyclodicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 1.0 g of 4-[6-acryloyloxyhexyloxy]benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The combined organic phases are washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which are pure according to thin-layer chromatography gives 0.9 g of 4-(4-[6-acryloyloxyhexyloxy]phenylcarbonyloxy)benzaldehyde.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C)C=O>[O:25]1[CH2:26][CH2:27][N:22]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (4 mL), morpholine (76.6 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 136.4 mg (86%) of methyl 3-morpholino-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.CCOCC>CS(C)=O>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([CH2:15][C:1]#[N:2])[CH:17]=[CH:18][CH:19]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: ClCc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CCc1cccc(OCc2ccccc2)c1

Procedure:
A solution of sodium cyanide (5.9 g.) in dimethyl sulphoxide (40 ml.) was treated with 3-benzyloxybenzyl chloride (23.2 g.) and the reaction mixture stirred and maintained at 60° for 1 hour. The mixture was poured into water and the product was isolated with ether in the usual manner to give 3-benzyloxyphenylacetonitrile, b.p. 162°-166°/0.55 mm.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([C@@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])(=[O:34])=[O:33])[CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([OH:45])=[CH:15][C:14]=1[CH2:13][CH2:12]3)(=[O:3])[CH3:2].S([O-])(O[CH3:50])(=O)=O.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([C@@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])(=[O:33])=[O:34])[CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:45][CH3:50])=[CH:15][C:14]=1[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)C[C@]12C
Reactant: COS(=O)(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)C[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reaction time: 1 h

Procedure:
2.9 cm3 of water is added to 1.05 g of the phenol obtained in Example 94 in solution in 3.9 cm3 of acetone, agitation is carried out, 0.3 cm3 of methyl sulphate and 0.83 cm3 of an 2N aqueous soda solution are added and agitation is carried out for 1 hour at ambient temperature. The reaction medium is acidified with 1 cm3 of 2N hydrochloric acid, poured into an aqueous solution of sodium bicarbonate, extracted with ethyl acetate, dried and the solvent is evaporated off. After chromatographing the residue on silica (eluant: ethyl acetate-cyclohexane 3-7), 959 mg of expected product is obtained.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=2)([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=2)[C:12]([CH:13]=[O:14])=[C:4]1[CH:1]([CH3:3])[CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1c(C=O)c2ccc([N+](=O)[O-])cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-isopropyl-6-nitro-1H-indole-3-carbaldehyde (Compound 121, 244 mg, 1.05 mmol) in DMF (10 ml) was added benzyl bromide (0.62 ml, 5.26 mmol) and K2CO3 (726 mg, 5.26 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])=[S:16]>>[CH:1]1([C:4]([NH2:7])=[O:5])[CH2:3][CH2:2]1.[CH3:21][O:20][C:18]([NH:17][C:15](=[S:16])[NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1)=[O:19]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)NC(=S)Nc1ccccc1N
Product: COC(=O)NC(=S)Nc1ccccc1
Product: NC(=O)C1CC1
Temperature: 25 °C

Procedure:
3.5g (0.033 mole) of cyclopropylcarbonylchloride were added slowly to 5.6g (0.025 mole) of 1-(2-aminophenyl)-3-methoxycarbonyl-2-thiourea in 30ml of tonuene at room temperature under agitation and the mixture was kept on reflux condition for an hour. The reaction mixture was cooled to room temperature and filtered with suction. The recovered colorless crystals were washed with water and dried. Then, by recrystallization of the crystals from the mixture of methanol and acetone, 4.2g of the crystals having the decomposition point of 191° - 192° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[O:12])[NH:7][C:6]=2[CH:21]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C.C[C:42]([CH3:44])=[O:43]>>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:11](=[O:12])[NH:10][C:8]1[NH:7][C:6]2[CH:21]=[C:2]([O:1][S:30]([C:24]3[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])(=[O:32])=[O:31])[CH:3]=[CH:4][C:5]=2[N:9]=1.[C:42]([OH:31])(=[O:43])[C:44]1[CH:4]=[CH:3][CH:2]=[CH:21][CH:6]=1
Reactant: O=C(NCc1ccccn1)Nc1nc2ccc(O)cc2[nH]1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)Nc1nc2ccc(OS(=O)(=O)c3c(F)cccc3F)cc2[nH]1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-pyridin-2-ylmethyl-urea (50 mg, example 83-a) and 2,6-difluoro-benzene-sulfonyl chloride (38 mg) in acetone (1 ml) was treated with triethylamine (48 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LC/MS triggered purification to give benzoic acid 2,6-difluoro-benzenesulfonic acid 2-(3-pyridin-2-ylmethyl-ureido)-3H-benzoimidazol-5-yl ester (29.6 mg) as a off-white solid Mass spectrum: 427 [M+H]+; retention time=7.86 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:37][C@H:38]1[O:42][C@@H:41]([C@H:43]([NH2:46])[CH2:44][CH3:45])[CH2:40][CH2:39]1>CC#N.CCO>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:46][C@@H:43]([C@H:41]2[CH2:40][CH2:39][C@@H:38]([CH3:37])[O:42]2)[CH2:44][CH3:45])=[CH:4][CH:3]=1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Reactant: CC[C@@H](N)[C@H]1CC[C@@H](C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CC#N
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (7 g, 17.91 mmol) in MeCN (2 ml) and EtOH (1 ml) under N2 at RT was added ((R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamine para-toluenesulfonate salt (Intermediate E) (5.67 g, 17.91 mmol) and TEA (0.999 ml, 7.16 mmol) and the reaction mixture was heated at 50° C. for 16 hours. Further TEA was added (2.48 ml, 17.91 mmol) and the reaction was heated at 50° C. for 1 hour then 60° C. for 20 hours. Further TEA (2.48 ml, 17.91 mmol) and Intermediate E (1.13 g, 3.58 mmol) was added and the reaction was heated at 60° C. for 17.5 hours. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and 1M HCl (aq). The aqueous layer was adjusted to pH 5 using 2M NaOH (aq) and extracted using EtOAc. The EtOAc layers were combined and washed with saturated sodium bicarbonate (aq), water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was recrystallised from toluene to give a light brown solid; [M+H]+ 488.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.3 (1H, m) 1.6 (3H, m) 1.9 (2H, m) 3.6 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (2H, m) 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.5 (1H, s), 10.1 (1H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1.[OH:23]P([O-])(O)=O.[K+].[OH:29]P(O)(O)=O.[Na+].[Cl-]>O>[OH:23][CH:3]1[CH2:4][C:5](=[O:1])[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)=[CH:2]1.[OH:29][CH:2]1[CH:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[C:5](=[O:1])[CH:4]=[CH:3]1
Reactant: O=P(O)(O)O
Reactant: OC(Cc1cccc(OCc2ccccc2)c1)c1ccco1
Reactant: O=P([O-])(O)O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C1C=CC(O)C1Cc1cccc(OCc2ccccc2)c1
Product: O=C1CC(O)C=C1Cc1cccc(OCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
1-(Furan-2-yl)-2-(3-benzyloxyphenyl)ethan-1-ol (3.97 kg, 13.49 mol) and KH2PO4 (120 g, 0.88 mol) was added to H2O (120 L) and H3PO4 was added until pH=3. The reaction was kept being stirred at 120° C. for 5 hours. After being cooled, NaCl (25 kg) was added, and the reaction was extracted with EtOAc, dried over MgSO4, and evaporated to give the crude 4-hydroxy-2-(3-benzyloxybenzyl)cyclopent-2-enone and 4-hydroxy-5-(3-benzyloxybenzyl)cyclopent-2-enone as black oil: 3.4 kg (crude yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@H]1CC[C@H](c2ccccn2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 18.5 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.30 g, 4.69 mmol), (1S,3S)-3-(2-pyridyl)cyclopentylamine (913 mg, 5.63 mmol) and triethylamine (1.30 mL, 9.33 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1S,3S)-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (364 mg, 19%) as a yellow powder.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:29]12([C:39]3[C:40]([O:51][SiH:52]([CH3:54])[CH3:53])=[C:41]([CH:44]=[CH:45][C:46]=3[C:47]([CH3:50])([CH3:49])[CH3:48])[CH:42]=O)[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2.O>C1COCC1>[C:29]12([C:39]3[C:40]([O:51][SiH:52]([CH3:54])[CH3:53])=[C:41]([CH:42]=[CH:9][CH2:8][CH:3]4[O:2][CH2:7][CH2:6][CH2:5][O:4]4)[CH:44]=[CH:45][C:46]=3[C:47]([CH3:50])([CH3:48])[CH3:49])[CH2:30][CH:31]3[CH2:37][CH:35]([CH2:34][CH:33]([CH2:32]3)[CH2:38]1)[CH2:36]2
Reactant: C[SiH](C)Oc1c(C=O)ccc(C(C)(C)C)c1C12CC3CC(CC(C3)C1)C2
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C[SiH](C)Oc1c(C=CCC2OCCCO2)ccc(C(C)(C)C)c1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
33 g (72.1 mmoles) of [2-(1,3-dioxan-2-yl)ethyl] triphenylphosphonium bromide are suspended in 100 ml of THF. The suspension is cooled to 0° C. and 8.5 g (75.6 mmoles) of potassium terbutylate are added in small amounts. The mixture is left to stand until its temperature reaches 20° C. It is then stirred for 1 hour at which point it is cooled to 0° C. There is then slowly added a solution of 3-(1-adamantyl)-4-tert.butyl-dimethylsilyloxybenzaldehyde in 100 ml of TMF. Once the addition has ended, the mixture is left to stand until its temperature reaches ambient temperature at which point it is stirred for 2 hours, then poured into water, and extracted with methylene chloride. The organic phase is decanted, washed with water, dried over MgSO4 and the solvents evaporated. The residue is purified by passage through a silica column (eluant: 50:50 mixture of CH2Cl2 and hexane), yielding 19.4 g (95% yield) of the expected mixture containing more than 90% of isomer Z, and less than 10% of isomer E.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Reactant: N
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O

Procedure:
4-Chloro-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (1.0 g, 3 mmol, Example 100) and 7% methanolic ammonia (30 mL) were placed in a steel pressure vessel at about 150-160° C. for 6 hours. The vessel was cooled to below room temperature and the reaction solution removed and treated with methanolic potassium hydroxide. The solution was then evaporated to a low volume and diluted with water. The resulting precipitate was collected, washed with water and dried to provide 0.7 g of the crude product as a solid. The crude product was recrystallized from a mixture of ethyl acetate and methanol to provide a colorless solid.
Reaction SMILES: [NH2:1][OH:2].C1C=NC2C3N=CC=CC=3C=CC=2C=1.[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[C:19]=1[C:20]#[N:21]>CO.O>[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([C:27]([F:30])([F:28])[F:29])[C:19]=1[C:20](=[N:1][OH:2])[NH2:21].[F:17][C:18]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([C:27]([F:30])([F:28])[F:29])[C:19]=1[C:20]([NH2:21])=[O:2]
Reactant: N#Cc1c(C(F)(F)F)ccc(F)c1F
Reactant: NO
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: CO
Product: NC(=NO)c1c(C(F)(F)F)ccc(F)c1F
Product: NC(=O)c1c(C(F)(F)F)ccc(F)c1F
Reaction time: 7 h

Procedure:
Into an SUS reaction vessel was placed a mixed solvent of 1.5 L of methanol-water (volume ratio 1:2, tap water was used as water) into which 99.09 g (1.50 mol) of 50% hydroxylamine aqueous solution and 198 mg (1.00 mmol) of o-phenanthroline were dissolved beforehand. Into the mixed solvent was added 103.56 g (500 mmol) of 2,3-difluoro-6-trifluoromethylbenzonitrile (I″). The reaction temprature stood at 60° C. for 7 hours and was returned to room temperature. In HPLC analysis of the reaction solution, it was shown that (I″) disappeared, 2,3-difluoro-6-trifluoromethylbenzamidoxime (II′) was mainly produced (yield 78.9%) and 2,3-difluoro6-trifluoromethylbenzamide (III′) was produced as a byproduct (yield 9.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:8])([F:10])[F:9])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[N:3]=1
Reactant: ClCCN1CCCCC1
Reactant: Cc1cc(C(F)(F)F)n(-c2ccc(O)cc2)n1
Agent: Cl
Product: Cc1cc(C(F)(F)F)n(-c2ccc(OCCN3CCCCC3)cc2)n1
Yield: 55 %

Procedure:
The title compound was prepared from 4-(3-Methyl-5-trifluoromethyl-pyrazol-1-yl)-phenol (0.1 g, 0.42 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.16 g, 0.88 mmol) using the general procedure C with a yield of 55% (80 mg); 1H NMR (400 MHz, CDCl3) 7.33 (d, J=9.2 Hz, 2H), 6.98 (d, J=9.2 Hz, 2H), 6.43 (s, 1H), 4.15 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12, 6 Hz, 2H), 2.53 (br, 4H), 1.61-1.47 (m, 6H); LC/MS (ESI): 94%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[C@H:10]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[NH:11][C:12](=[O:25])[C@H:13]([CH:22]([CH3:24])[CH3:23])NC(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:44](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:61]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[C@H:62]([C:64](OC1C=CC([N+]([O-])=O)=CC=1)=[O:65])[CH3:63]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:41])[C@H:10]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[NH:11][C:12](=[O:25])[C@H:13]([CH:22]([CH3:23])[CH3:24])[NH:44][C:64](=[O:65])[C@H:62]([CH3:63])[NH:61][C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
The Boc group was removed from a sample (3.8 g, 6.6 mmole) of compound XX as described above. The partially deprotected 2-peptide ester (trifluoroacetate salt) was dissolved in DMF (60 ml) and treated with DIEA (2.4 ml, 15 mmole), HOBt (1.18 g, 7.7 mmole) and Boc-L-Ala-ONp (2.38 g, 7.7 mmole, Bachem) at 0°. After overnight storage at room temperature a semisolid mass formed. Most of the solvent was removed in vacuo, the residue triturated with EtOAc and with ether and dried: 3.6 g (85%), m.p. 140°-143° C.; [α]D23 -21.8° (c 0.8 DMF); RfB, 0.85; RfI, 0.62.