Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@H](c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.3871 mmol) in 1,2-dichloroethane (2.0 mL) was charged with 1-methylpiperazine (58.16 mg, 0.5807 mmol) and sodium triacetoxyborohydride (164.1 mg, 0.7743 mmol). The reaction mixture was stirred at rt for 24 hours. The reaction mixture was quenched with NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow oil. The crude material was purified and by silica gel chromatography on the combi-flash Rf system using DCM/7M NH3 in MeOH (100:0→90:10) as eluent to afford the cis isomer (76.5 mg, 58%, first eluting product) and the trans isomer (30.0 mg, 23%, second eluting product). Cis isomer: 1H NMR (CDCl3, 400 MHz): δ=1.42-1.56 (m, 4 H), 1.82-1.96 (m, 2 H), 2.06 (d, J=11.87 Hz, 2 H), 2.27 (br. s., 1 H), 2.34 (s, 3 H), 2.38-2.78 (m, 9 H), 3.14 (s, 3 H), 4.31 (s, 2 H), 5.08 (s, 2 H), 6.58 (d, J=8.34 Hz, 1 H), 7.18 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 343.25 [MH+]. Trans isomer: 1H NMR (CDCl3, 400 MHz): δ=1.35-1.75 (m, 7 H), 1.91 (d, J=12.13 Hz, 2 H), 2.03-2.13 (m, 2 H), 2.34 (s, 3 H), 2.47-2.82 (m, 7 H), 3.14 (s, 3 H), 4.28 (s, 2 H), 5.09 (s, 2 H), 6.56 (d, J=8.34 Hz, 1 H), 7.09 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 343.26 [MH+].
Reaction SMILES: [NH2:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:5]2[N:4]([CH2:11][CH2:12][CH3:13])[C:3]1=[O:14].[C:15]([O:18][CH:19]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:20]=O)(=[O:17])[CH3:16].C([O-])(=O)C.[Na+]>CO>[OH:10][CH:8]1[CH2:7][CH:6]2[N:2]([N:1]=[CH:20][CH:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[O:18][C:15](=[O:17])[CH3:16])[C:3](=[O:14])[N:4]([CH2:11][CH2:12][CH3:13])[CH:5]2[CH2:9]1
Reactant: CC(=O)OC(C=O)C1CCCCC1
Reactant: CCCN1C(=O)N(N)C2CC(O)CC21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCN1C(=O)N(N=CC(OC(C)=O)C2CCCCC2)C2CC(O)CC21
Temperature: 15 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
A solution of the compound of step (g) (5.0 g) and 2-acetoxy-2-cyclohexylacetaldehyde (Ross et al, J. Med. Chem., 22, 412 (1979), 6.0 g) in methanol (175 ml) containing sodium acetate (3.64 g) was stirred at 15° C. under a nitrogen atmosphere for 16 hours. The alcohol was removed in vacuo and water (100 ml) and chloroform (100 ml) added. The organic phase was separated and washed with brine (100 ml), then dried over anhy. sodium sulphate. Filtration and concentration of the filtrate in vacuo gave a yellow oil (10.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:31]OS([O-])=O.[K+]>CC(C)=O.O.C(=O)(O)[O-].[Na+]>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N+:27]([O-:31])=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)=[CH:10][C:2]=1[Cl:1])(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5c(ccc[n+]5[O-])c4)c3n2)cc1Cl
Yield: 28.9 %

Procedure:
To a solution of example 108 (0.100 g, 0.241 mmol) in acetone (0.6 ml), oxone (0.74 g, 1.20 mmol) in water (2 ml) was added and heated under reflux for 20 h. The mixture was diluted with aqueous 10% sodium bicarbonate solution and extracted with dichloromethane, the organic layer dried over anhydrous sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound (0.030 g, 29%) as a pale brown solid. M.P.: 182-183° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.71 (d, J=8.8 Hz, 1H), 8.55 (d, J=6.1 Hz, 1H), 8.52 (d, J=9.1 Hz, 1H), 8.29 (s, 1H), 8.23 (m, 2H), 8.12 (s, 1H), 7.95-7.83 (m, 3H), 7.67 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.47 (dd, J=8.4, 6.2 Hz, 1H), 6.24 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9]=[O:10].[CH3:11][Mg]Cl.Cl.[Mg]>C1COCC1.O>[CH3:11][CH:9]([OH:10])[CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=CCCc1ccccn1
Reactant: C[Mg]Cl
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CCc1ccccn1
Reaction time: 1 h

Procedure:
Dimethyl sulphoxide (3.3 ml) was added dropwise to a solution of oxalyl chloride (3.9 ml) in dichloromethane (25 ml) at -78° under nitrogen. After gas evolution had ceased (5 min) a solution of 2-pyridinepropanol (4.0 g) in dichloromethane (20 ml) was added over 5 min and the solution stirred at -78° for 20 min. Triethylamine (5 ml) was added dropwise to the solution, then the resulting dark green mixture warmed to 20° and washed with 2M sodium carbonate solution (20 ml). The organic phase was dried and evaporated in vacuo to give 2-pyridinepropanal. This aldehyde was immediately dissolved in THF (30 ml) and added dropwise to a 3M solution of methylmagnesium chloride in THF (20 ml) at 0°-5° under nitrogen. After 1 h, water (10 ml) was cautiously added followed by sufficient 2M hydrochloric acid to dissolved all the magnesium residues (resulting pH~7 ). The solution was extracted with dichloromethane (3×30 ml) and the organic extracts dried and evaporated in vacuo to a dark oil. Kugelrohr bulb to bulb distillation (b.p. 130°-135°/0.7 mm) afforded the title compound as a pale yellow oil (0.91 g), t.l.c. ethyl acetate Rf 0.17.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:20]N1C(=O)CCC1=O>O1CCCC1.C(Cl)(Cl)Cl>[Br:20][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-phenylmalonate (15 ml) in 200 ml of tetrahydrofuran, kept at 0° C. and under nitrogen atmosphere, 3.475 g of sodium hydride are added and the mixture is kept 30 minutes under stirring at 0° C., then it is brought to room temperature. After cooling again to 0° C., the reaction mixture is added with 14.3 g of N-bromosuccinimide. After about 15 minutes, the white solid which separated is filtered off and the filtrate is concentrated to dryness to give a residue which is redissolved in chloroform and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give 15.66 g of the product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:11]CCl>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:11])=[N:5][OH:6]
Reactant: ON=Cc1ccccc1F
Reactant: ClCCl
Product: ON=C(Cl)c1ccccc1F
Temperature: -10 °C

Procedure:
In 1 liter dichloromethane was dissolved 55.0 g 2-fluorobenzaldehyde oxime at room temperature with stirring. The resulting solution was cooled to -10° C. and Cl2 was bubbled in at such a rate to maintain temperature below 15° C. After a dark blue color was generated (2-3 minutes) a solution of triethylamine (50 ml) in dichloromethane (100 ml) was added dropwise concurrently with Cl2 addition. When the reaction mixture had maintained a yellow color, additions of the triethylamine solution and Cl2 were discontinued. Concentration of the reaction mixture left an oil which was dissolved in ether and washed four times with 3N HCl followed by a final wash with brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 60.0 g of 2-fluoro-N-hydroxybenzenecarboximidoyl chloride as an oil which solidified on standing.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].O>CS(C)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:10](=[O:5])[C:11]([O:13][CH3:14])=[O:12])=[CH:16][CH:17]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(=O)c1ccc(Cl)cc1
Temperature: 22.5 °C
Reaction time: 24 h

Procedure:
97.2 g of a 75% strength aqueous N-methylmorpholine N-oxide solution were added with ice-cooling to a solution of 100 g (0.38 mol) of the compound of Example 1 in 400 ml of dimethyl sulfoxide (DMSO). After the mixture had been stirred for 24 hours at 20 to 25° C., it was poured into water and extracted with methyl tert-butyl ether (MtBE). After the organic phases had been dried, stripped from the solvent and chromatographed on silica gel (cyclohexane/MtBE [3:1]), 69 g of the title compound was obtained.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:13]=3[O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25]([C:33]4[N:34]=[CH:35][S:36][CH:37]=4)C(=O)OC(C)(C)C)(=[O:24])=[O:23])=[C:17]([F:38])[CH:16]=3)[CH:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.Cl>ClCCl.O1CCOCC1>[N:1]1([CH2:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:13]=3[O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:33]4[N:34]=[CH:35][S:36][CH:37]=4)(=[O:23])=[O:24])=[C:17]([F:38])[CH:16]=3)[CH:9]=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(CN3CCC3)c2)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cscn1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(CN3CCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl [(4-{2-[2-(azetidin-1-ylmethyl)pyridin-4-yl]-4-chlorophenoxy}-2,5-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate, (Preparation 878, 0.325 g, 0.0005 mol) was dissolved in dichloromethane (3 mL) then 4 molar hydrogen chloride in 1,4-dioxane (3 mL) was added. The reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the crude product purified by preparative HPLC to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([SH:8])[CH:7]=1.Cl[C:14]1[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([S:8][C:14]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])[CH:7]=1
Reactant: O=C(O)Cc1cc(S)cc(Cl)c1
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)cc(CC(=O)O)c2)c(C#N)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from step (i) and the product from example 12 step (i).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:13]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([NH2:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 2,4-dichloroquinazoline (2.0 g, 10 mmol) in THF (10 mL), was added ammonia (28-30% in water, 18 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated. The resulting solid was washed with EtOAc to give the title compound (1.3 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.52-7.48 (m, 1H), 7.6-7.58 (m, 1H), 7.8-7.76 (m, 1H), 8.22-8.20 (m, 1H), 8.32 (bs, 2H).
Reaction SMILES: [C:1]([CH:3]([Na])[C:4](=[O:6])[CH3:5])#[N:2].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:11]=1[CH3:20]>CN(C)C=O.[Cl-].[NH4+]>[CH3:20][C:11]1[C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH:3]([C:4](=[O:6])[CH3:5])[C:1]#[N:2]
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: CC(=O)C([Na])C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)C(C#N)Cc1cccc(C(F)(F)F)c1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of (1-cyano-2-oxopropyl)sodium (3.5 g, 33.2 mmol) in N,N-Dimethylformamide (25 mL) stirred under nitrogen at 0° C. was added a solution of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (7.0 g, 27.7 mmol) in 10 ml of DMF dropwise during 30 min. The reaction mixture was stirred at 40° C. for 2 hours. Then this solution was diluted with saturated ammonium chloride solution. This solution was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried, concentrated to dryness in vacuo. The crude product was purified with on a silica gel column to give 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3-oxobutanenitrile. (5.2 g, 74%). To a solution of 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}3-oxobutanenitrile (5.2 g, 20.4 mmol) in ethanol (400 mL) stirred under nitrogen at 20° C. was added neat hydrazine monohydrate (2.25 g, 30.6 mmol) dropwise during 5 minutes. The reaction mixture was stirred at 100° C. for overnight. After cooled to room temperature, the reaction mixture was evaporated to dryness in vacuo. The residue was purified on a silica gel column (methanol/DCM gradient solvent system) to provide titled product. (2.16 g, 39%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (s, 3H) 2.39 (s, 3H) 3.63 (s, 2H) 4.30 (br. s., 2H) 7.19 (d, J=7.58 Hz, 1H) 7.27 (t, J=7.71 Hz, 1H) 7.49 (s, 1H) 11.09 (br. s., 1H)
Reaction SMILES: O[CH:2]1[O:6][C:5](=O)[CH:4]=[C:3]1[CH3:8].Cl.[NH:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH2:11]>C(O)C>[CH3:2][C:3]1[CH:8]=[N:11][N:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[O:6])[CH:4]=1
Reactant: CC1=CC(=O)OC1O
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1ncc(C)cc1=O

Procedure:
5-Hydroxy-4-methylfuran-2(5H)-one (1.19 g, 10.4 mmol) and ethyl hydrazinoacetate hydrochloride (1.61 g, 10.4 mmol) in 95% ethanol (20 mL) was refluxed for 2 h. Removal of the solvent in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl [4-methyl-6-oxopyridazin-1(6H)-yl]acetate as a yellow crystalline. LC/MS 219.2 (M+23).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[CH2:21]([O:23][C:24](=[O:37])[C:25]([O:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][C:30]=1[CH3:36])([CH3:27])[CH3:26])[CH3:22].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH2:21]([O:23][C:24](=[O:37])[C:25]([CH3:27])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:10][CH2:9][CH2:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:5][CH:6]=2)=[CH:31][C:30]=1[CH3:36])[CH3:26])[CH3:22]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
0.181 g (0.642 mmol) of the above prepared 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol and 0.153 g (0.642 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 8 ml of abs. THF and treated successively at 0° C. with 0.156 g (0.771 mmol) of tributylphosphine and 0.133 g (0.770 mmol) of N,N,N′,N′-tetramethylazodicarboxamide. The cooling bath was then removed and stirring continued for one night. Filtration over a pad of Celite, evaporation of the solvent, followed by flash chromatography (SiO2, hexane/AcOEt=85/15), delivered 0.070 g of the title compound as colorless oil.
Reaction SMILES: [I:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:3]1[C:2]([I:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(I)c1

Procedure:
3-Iodo-5-nitropyridin-2-ol (3.00 g, 0.0113 mol) was heated to reflux in phosphoryl chloride (15 mL, 0.1609 mol) for 4 hours. The reaction was quenched in ice/water and was neutralized with Na2CO3. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo to give the product, which was used in the next reaction without purification.
Reaction SMILES: S(O[CH2:12][C:13]1([C:26]([O:28][CH3:29])=[O:27])[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][NH2:41]>C(#N)C>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][NH:41][CH2:12][C:13]1([C:26]([O:28][CH3:29])=[O:27])[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CN(C(=O)OC(C)(C)C)CCO1
Solvent: CC#N
Product: COC(=O)C1(CNCc2ccc(OC)cc2OC)CN(C(=O)OC(C)(C)C)CCO1
Reaction time: 15 h
Yield: 31.9 %

Procedure:
E4 (365 mg, 0.850 mmol) was dissolved in acetonitrile (10 mL), (2,4-dimethoxyphenyl)methanamine (700 μL, 4.66 mmol) was added and the solution was stirred for 15 h at reflux temperature. The reaction mixture was concentrated in vacuo, extracted with water/EtOAc and washed twice with water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography from toluene:EtOAc 100:0 to 20:80 which gave the title compound (115 mg, 32%). MS (ES) C21H32N2O7 requires: 424. found: 425.2 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Product: O=C(NC(CCN1CCOCC1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and morpholine, the title compound was obtained in 99.3% purity by HPLC.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH2:39]([O:41][C:42]1[C:51]([C:52](O)=[O:53])=[C:50]([CH3:55])[C:49]2[C:44](=[CH:45][C:46]([C:56]([F:59])([F:58])[F:57])=[CH:47][CH:48]=2)[N:43]=1)[CH3:40]>C1COCC1.CCOC(C)=O>[CH2:39]([O:41][C:42]1[C:51]([C:52]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:53])=[C:50]([CH3:55])[C:49]2[C:44](=[CH:45][C:46]([C:56]([F:59])([F:57])[F:58])=[CH:47][CH:48]=2)[N:43]=1)[CH3:40]
Reactant: CCOc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Reactant: NCc1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)NCc1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
53 μl (0.5 mmol) thiophene methane amine, 172 mg (0.5 mmol) HATU and 165 μl (1.2 mmol) NEt3 were added consecutively to a solution of 123 mg (0.4 mmol) 2-ethoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid in THF (3 ml) and thereafter stirred for 16 h at RT. The solution was subsequently diluted with EtOAc and washed with a 4N aq. NH4CL sol., a 1M aq. Na2CO3 sol. and brine. The organic phase was dried over MgSO4, filtered through silica gel and concentrated in a vacuum. 116 mg (0.3 mmol, 72%) 2-ethoxy-4-methyl-N-(thiophene-2-yl-methyl)-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 2) was obtained as a residue. MS: m/z 395.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[O:21][CH3:22])=O)C.[Li+].[Cl-].[Li+].[BH4-]>C1COCC1>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:8]2[C:7]([O:21][CH3:22])=[C:6]([CH2:4][OH:3])[S:20][C:9]=2[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1sc2c(c1OC)CCN(C(=O)OCC)CC2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2sc(CO)c(OC)c2CC1
Reaction time: 1 h

Procedure:
The product of step c) (2.5 g, 7.8 mmol) was dissolved in 125 mL dry THF and treated with LiCl (0.65 g, 15.3 mmol) followed by LiBH4 (15.3 mL of 2M). After stirring for 1 hour, the reaction was quenched carefully with EtOH and HOAc till no gas evolution was observed. The crude reaction mixture was partitioned between water and DCM. The organic extract was dried over MgSO4 and concentrated to give 2.3 g of a clear oil which was purified by silica chromatography (30% EtOAc/Hex) to give 1.03 g of the subtitle compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.ClCCCl.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].C(Cl)(Cl)Cl>O>[CH2:27]([S:29]([N:19]1[CH2:18][CH2:17][N:16]([C:12]2[C:11]([F:22])=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:20]1)(=[O:31])=[O:30])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Reactant: CCS(=O)(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CCS(=O)(=O)N1CCN(c2cccc(CO)c2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (140 mg) was mixed with DCE (4 ml), and ethanesulfonyl chloride (122 mg) and TEA (145 mg) were added thereto, followed by stirring at room temperature for 2 hours. CHCl3 and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (4 ml), and a 1 M TBAF/THF solution (0.9 ml) was added thereto, followed by stirring at room temperature for 2 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain {3-[4-(ethylsulfonyl)piperazin-1-yl]-2-fluorophenyl}methanol (123.9 mg).