Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Cl-:24].CN(C=O)C>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([Cl:24])=[O:23])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [Cl-]
Reactant: O=C(O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2cc(-c3cccc4cnccc34)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(isoquinolin-5-yl)-1-naphthoic acid (0.123 g, 0.4 mmol) was suspended in CH2Cl2 (15 mL) and oxallyl chloride was (0.036 mL, 0.4 mmol) was added followed by a drop of DMF. The resulting mixture was stirred at room temperature overnight and the solvent was evaporated to give a solid. The solid was dried under vacuum.
Reaction SMILES: [H-].[Na+].[C:3]1(=O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]C1.CI.C([O:19][CH2:20][CH3:21])(=O)C.[CH3:22]CCCCC>C1COCC1>[CH3:22][C:6]1([CH3:5])[CH2:7][CH2:8][C:9]2[C:21](=[CH:3][CH:12]=[CH:11][CH:10]=2)[C:20]1=[O:19]
Reactant: CCOC(C)=O
Reactant: O=C1CCCc2ccccc21
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a suspension of NaH (8.2 gm, 343 mmol) in THF (250 mL) in a one-liter round bottomed flask, 1-tetralone [11] (10.0 gm, 69 mmol) dissolved in dry THF (25 mL) was added. After stirring the mixture for 10 minutes at RT, methyl iodide (11.1 ml, 178 mmol) was added via a syringe. The mixture was heated on an oil bath to 40° C. for 30 minutes, and stirring continued at RT until the starting material disappeared. The reaction was monitored by TLC using ethyl acetate:hexane (1:6) solvent mixture. The reaction was quenched by addition of water (slowly and dropwise) to destroy excess sodium hydride. The mixture was extracted with ethyl acetate, washed with water and dried over sodium sulphate. Evaporation of the solvent yielded a brown oil. Column chromatography using silica gel with EtOAc:Hexane (1:6) afforded clean 2,2-dimethyl-1-tetralone [12](10.8 g, 83%).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:23]([C:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[CH:28]=[C:27]([Sn:38]([CH3:41])([CH3:40])[CH3:39])[CH:26]=1)=[O:24].S([O-])([O-])(=O)=[O:43].[Na+].[Na+].CCOCC>N1C=CC=CC=1>[C:23]([C:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[CH:28]=[C:27]([Sn:38]([CH3:41])([CH3:40])[CH3:39])[CH:26]=1)([OH:43])=[O:24]
Reactant: C[Sn](C)(C)c1cc(C=O)c2c(c1)oc1ccccc12
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[Sn](C)(C)c1cc(C(=O)O)c2c(c1)oc1ccccc12
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of tetra-n-butylammonium permanganate (5.1 g, 14.0 mmol) in anhydrous pyridine (35 mL) was transferred via cannula needle into a solution of the stannane 305 (5.0 g, 14.0 mmol) in anhydrous pyridine (35 mL) at 0° C. under a nitrogen atmosphere. The reaction was stirred for 30 min., then saturated aqueous sodium sulfate (50 mL) was added to quench the reaction. The mixture was then poured into ether and the layers separated. The organic layer was washed with 2N aqueous HCl (6 times with 100 mL), water (2 times) and then brine (2 times). The solution was dried with magnesium sulfate, then filtered and concentrated under vacuum to provide 4.8 g (92% yield) of the stannane 306 as a white solid.
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)C1C=CC=CC=1.C1CC=CCC=1>[Pd].O.C(O)C>[C:17]1([C@:9]23[NH:8][C@H:13]([CH2:14][CH2:15]2)[CH2:12][CH2:11][C@H:10]3[OH:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: C1=CCC=CC1
Product: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Temperature: 60 °C
Yield: 60 %

Procedure:
10% Palladium on carbon (4 g) was added as a slurry in water (25 ml) to a solution of (1R*,2R*,5R*)-8-benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 29.3 g, 100 mmol) and 1,4-cyclohexadiene (80 g, 1 mol) in ethanol (250 ml). The mixture was heated at 60° C. for 6 hours. On cooling to room temperature the mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5 and 10% methanol/dichloromethane/1% ammonia to yield the title compound (12.2 g, 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCC1CC(c2ccc(F)c(F)c2)=NO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC1CC(c2ccc(F)c(F)c2)=NO1
Reaction time: 0.5 h

Procedure:
(5RS)-3-(3,4-Difluorophenyl)-5-hydroxymethyl-4,5-dihydroisoxazole (3.79 g, 17.8 mM) was dissolved in anhydrous dichloromethane (200 ml) under a nitrogen atmosphere, cooled to 0°, and treated with triethylamine (2.51 g, 24.9 mM). Methanesulfonyl chloride (2.45 g, 21.4 mM) was added dropwise with stirring during a period of 30 minutes, then the mixture allowed to come to ambient temperature over 2 hours. The mixture was treated with water (200 ml), the organic layer separated, and washed with aqueous hydrochloric acid (2N, 100 ml), sodium bicarbonate (100 ml), and brine (200 ml). After drying (magnesium sulfate) and evaporation, the desired product was obtained as a white solid (4.85 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][CH2:25][CH2:26][NH:27][CH3:28])=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:23]=[N:22][C:21]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:16])=[N:20][CH:19]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: CNCCNc1ncc(Br)cn1
Product: Cc1nc(C(=O)N(C)CCNc2ncc(Br)cn2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4carboxylic acid (78 mg, 0.33 mmol) and N-(5-bromo-pyrimidin-2-yl)-N′-methyl-ethane-1,2-diamine, D11 (76 mg, 0.33 mmol), according to the procedure described for Example 1, as a solid (105 mg, 71%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23](Cl)=[O:24])[CH2:19][CH2:18]1.[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:3]3[CH:2]=[CH:1][C:6]([NH:7][C:37](=[O:38])[C:36]4[CH:35]=[CH:34][C:33]([N:30]5[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]5)=[CH:41][CH:40]=4)=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)=[O:24])[CH2:19][CH2:18]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: O=C(Cl)N1CCC(O)CC1
Reactant: Nc1ccc(Nc2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(Nc2ccc(NC(=O)N3CCC(O)CC3)cc2)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 792 was prepared according to the procedure described in Scheme IV from 4,4′-diaminodiphenylamine, (4-hydroxypiperidin-1-yl)carbonyl chloride, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C30H35N5O4: 530.28; found: 530.04.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([C@:26]([NH:42]C(=O)OC(C)(C)C)([CH3:41])[CH2:27][O:28][P:29]([O:36]C(C)(C)C)([O:31]C(C)(C)C)=[O:30])[CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.Cl.CCOCC>O>[P:29]([OH:31])([OH:36])([O:28][CH2:27][C@:26]([NH2:42])([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([S:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:17]=2)[CH:22]=1)[CH3:41])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Yield: 4 %

Procedure:
(R)-tert-butyl 2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)-1-(di-tert-butoxyphosphoryloxy)propan-2-ylcarbamate was dissolved in acetic acid (2.0 mL, 0.035 mol) and 10 M hydrogen chloride in water (0.5 mL) and stirred for 1 d. Removal solvent and concentration gave an oil, which was added to water and ether. The aqueous layer was concentrated and purified by preparative HPLC 0.1% TFA water/ACN to give (R)-2-amino-2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)propyl dihydrogen phosphate as a solid (1.1 mg, 4%). LCMS 1.56 496.25 (M+1, 40%), 991.66. HNMR shows quite pure. 1H NMR (400 MHz, MeOD) δ=7.98 (s, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.82 (s, 1H), 7.65 (d, J=6.7 Hz, 1H), 7.43 (d, J=10.4 Hz, 1H), 7.39-7.25 (m, 6H), 7.05-6.95 (m, 3H), 5.06 (s, 2H), 4.29 (dd, J=5.0, 11.0 Hz, 1H), 4.16 (dd, J=5.4, 11.0 Hz, 1H), 1.86 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:7][N:8]=[N+:9]=[N-:10])=[O:6])=[N+:2]=[N-:3].[N-:11]=[N+:12]=[N-:13].[Na+].[CH3:15]C(C)=O>>[N:1]([CH2:4][C:5]([OH:6])([CH2:15][N:11]=[N+:12]=[N-:13])[CH2:7][N:8]=[N+:9]=[N-:10])=[N+:2]=[N-:3]
Reactant: CC(C)=O
Reactant: [N-]=[N+]=NCC(=O)CN=[N+]=[N-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC(O)(CN=[N+]=[N-])CN=[N+]=[N-]

Procedure:
To a solution of 1,3-diazidoacetone 7(10 gms, 0.07 mol) in aq. acetone (20 mL water, 150 mL acetone) was added sodium azide (15 gm, 0.23 mol) and the resulting mixture was heated under reflux for 14 hours. The reaction mixture was concentrated under reduced pressure and partitioned between water and methylene chloride. The organic layer was separated, dried over sodium sulfate and concentrated to obtain a residue that was chromatographed to obtain pure 2-azidomethyl-2-hydroxy-1,3-diazidopropane 2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].Cl>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(O)c(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 99 %

Procedure:
A 200 mL round bottomed flask is charged with 2-(benzyloxy)-1-methoxy-4-nitrobenzene (10.00 g, 38.6 mmol) and DMSO (30 mL). To the stirred suspension is added NaOH (10 N, 10 mL, 100 mmol), and the mixture is heated to 100° C. for 5 h. The solution is cooled to rt, and immersed in a water ice bath, and water (30 mL) is added to the solution. The pH is adjusted to ˜1 by addition of concentrated HCl (10 mL, 121 mmol). The solution is extracted once with toluene (80 mL). The organic phase is washed successively with water (20 mL) and brine (20 mL), and evaporated to dryness yielding 9.37 g (99%) of the title compound as a yellow solid. LCMS (Standard Method): 2.70 min, 268 (M+Na)+. 1NMR (300 MHz, CDCl3) δ 7.92-7.86 (m, 2H), 7.45-7.41 (m, 5H), 7.00 (d, J=8.8 Hz, 1H), 5.20 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH3:12]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Solvent: C1COCCO1
Product: NC(=O)Cc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 109 %

Procedure:
Add 2-(4-bromo-phenyl)-acetyl chloride (1.00 g, 4.28 mmol) to a solution of ammonia in dioxane (0.5 M, 15 mL) at room temperature. Stir for 30 min., then quench with water. Extract with DCM (10 mL) and pass through an IST Phase Separator Frit® and concentrate until precipitate appears. Collect precipitate by filtration, wash powder with DCM, then dissolve in methanol, filter and concentrate to give a white powder (1.0 g, 109%). 1H-NMR (300 MHz, MeOD) δ 7.48 (d, 2H), 7.25 (d, 2H), 3.50 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]4[C:32]([CH3:34])([CH3:33])[O:31]C(C)(C)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2].O.Cl>CCO>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[C:32]([CH3:34])([OH:31])[CH3:33])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)C(C)(C)O)ns1
Yield: 92.9 %

Procedure:
To a mixture of (S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (0.134 g, 0.255 mmol) in EtOH (5 ml) and water (0.227 ml, 0.255 mmol) was added concentrated HCl (0.0531 ml, 0.637 mmol) and the reaction heated at reflux for 5 hours. The reaction was concentrated to a residue that was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The combined organic layers were dried over Na2SO4, filtered and concentrated to give (S)-1-(5-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-2-methylpropane-1,2-diol (0.115 g, 92.9% yield) as a white solid. Mass Spectrum (apci) m/z=468.1 (M+H—H2O).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6]/[C:7]/2=[CH:12]\[C:13]([O:15]CC)=O.IC1C=CC=C2C=1[CH2:21][CH2:22][N:23]=C2C.[Li+].CC([N-]C(C)C)C.C(=O)(OCC)[O:39]CC>C1COCC1>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:21](=[O:39])[CH2:22][NH:23][C:13](=[O:15])[CH:12]=[C:7]12
Reactant: CC1=NCCc2c(I)cccc21
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)/C=C1\NCCc2c(I)cccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
(Z)-ethyl 2-(5-iodo-3,4-dihydroisoquinolin-1(2H)-ylidene)acetate. To a yellow cooled solution of 5-iodo-1-methyl-3,4-dihydroisoquinoline (30.1 g, 111 mmol) in dry THF (900 mL) was added dropwise a solution of LDA (2M in THF, 111 mL, 222 mmol) at −78° C. The resulting brown solution was stirred for at −78° C. for 45 min and a solution of diethyl carbonate (14 mL, 116 mmol) in THF (80 mL) was then added dropwise. The mixture was stirred at −78° C. for another 45 min, and then poured onto brine. The resulting yellow suspension was filtered and the filter cake was washed with AcOEt. The filtrate was extracted with AcOEt, and the combined org. phases were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (40.0 g) as a brown oil that was used as it is in the next step. UPLC-MS: MS 344.1 (M+H+); UPLC rt 1.28 min.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[OH:9].[Cr](O[Cr](O)(=O)=O)(O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2=[O:9]
Reactant: C[C@@]12CCC(CC1O)C2
Agent: O=[Cr](=O)(O)O[Cr](=O)(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@@]12CCC(CC1=O)C2
Reaction time: 72 h
Yield: 64.5 %

Procedure:
79.6 g (0.63M) of the optically active alcohol (V) obtained in 1-4) above was dissolved in 300 ml of methylene chloride and the resulting solution was added dropwise to a suspension of 304 g (0.81M) of pyridine dichromate in 700 ml of methylene chloride at room temperature. Then the resulting mixture was stirred for three days. The obtained reaction mixture was diluted with 1 l of diethyl ether and filtered through celite. The filtrate was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was distilled under reduced pressure to give 50.4 g (theoretical yield: 64.5%) of the aimed compound (VI) as a colorless oily material. b.p.: 70° C./20 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9](Cl)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[Cl:12])=[O:5])[CH3:2].[CH2:18]([NH:25][CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:12][C:11]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([N:25]([CH2:26][CH3:27])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=[C:7]([CH3:17])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCNCc1ccccc1
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N(CC)Cc2ccccc2)c([N+](=O)[O-])c1Cl
Reaction time: 24 h

Procedure:
279 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester are dissolved in 700 ml. of alcohol. 150 g. of triethylamine are added and at reflux temperature 135 g. of benzyl(ethyl)amine are slowly dropped in. After the addition is completed, the heating is continued for another hour. After this time, the solvent is removed in vacuo, 300 ml. of water are added and the mixture extracted three times with 200 ml. portions of ether. The organic layers are combined, dried with calcium chloride and the solvent is distilled off. The resulting oil is distilled in vacuo, b.p.0.05 210°-220°. The crude product is dissolved in 300 ml. of ether and cooled to about -50°. After 24 hours, the isomeric compound 6-chloro-4-[ethyl(phenylmethyl)amino]-2-methyl-5-nitro-3-pyridinecarboxylic acid ethyl ester precipitates, is filtered off and the filtrate evaporated to dryness. The resulting 4-chloro-6-[ethyl(phenylmethyl)amino]-2-methyl-5-nitro-3-pyridinecarboxylic acid, yield 215 g. (56%) is used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>C(Cl)(Cl)Cl.CS(C)=O>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([O:35][C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2C
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn2c3c(c(OC4CCN(C(=O)OC(C)(C)C)C4)c(F)cc3c1=O)OCC2C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.3 %

Procedure:
To a mixture of 263 mg of ethyl 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine6-carboxylate, 318 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 194 mg of DBU and 3 ml of DMSO was added 74 mg of 55% sodium hydride while the former was stirred at room temperature for 2.5 hours. After the resultant mixture was stirred at room temperature, the reaction mixture was diluted with chloroform and then successively washed with 10% citric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness. The residue was purified by chromatography on silica gel (chloroform/methanol: 100/1), whereby 220 mg of ethyl 10-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-9-fluoro2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylate was obtained.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH2:34][CH2:33]1>>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:34][CH2:33]1
Reactant: CN1CCN(CCCCN)CC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-(4-methyl-piperazin-1-yl)-butylamine by the procedure analogous to Example 1. MS (APCl, m/z): 515 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:43])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:25](=[O:42])[C@@H:26]([NH:34]C(OC(C)(C)C)=O)[CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:43])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:25](=[O:42])[C@@H:26]([NH2:34])[CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)[C@@H](N)CC1CCCCC1

Procedure:
A solution of 1-[2-(S)-[[2-(S)-[[(1,1-dimethylethoxy)-carbonyl]amino]-1-oxo-3-cyclohexylpropyl]amino]-4-methylpentyl]-L-proline 4-phenylbutylamide (62.8 mg, 104 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (3.0 mL). After TLC indicated the reaction was complete, the mixture was concentrated to a residue, taken up in fresh dichloromethane (10 mL) and washed with satd. aq. NaHCO3 and dried (MgSO4). The solution was concentrated to an oil and chromatographed with acidic silica to provide 48.8 mg of the the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[NH3:28]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 50 g. of sodium 4-acetylbenzenesulfonate is added in portions, with stirring, to 500 ml. of concentrated aqueous ammonia. The mixture is stirred at room temperature for 16 hours, cooled, and the precipitated 4-acetylbenzenesulfonamide removed by filtration and crystallized from aqueous ethanol/acetone; m.p. 177-179° C.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:29]([OH:32])([CH3:31])[CH3:30])[CH:19]=[N:20][C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][C@H:24]([CH3:28])[CH2:23]1>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:29]([OH:32])([CH3:31])[CH3:30])[CH:19]=[N:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([C:2]2[NH:3][C:4]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=3[N:6]=2)[C@H:24]([CH3:28])[CH2:23]1
Reactant: C[C@@H]1CN(c2ncc(C(C)(C)O)cc2Cl)CCN1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Solvent: CCO
Product: C[C@@H]1CN(c2ncc(C(C)(C)O)cc2Cl)CCN1c1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (58 mg, 0.26 mmol, Example 1c) and 2-[5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl]-propan-2-ol from step (c) above (90 mg, 0.33 mmol) in ethanol (1 mL) reacted under the conditions of Example 3c to give the title compound. MS (ESI, pos. ion) m/z: 454 (M+1).