Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][O:40][CH2:41][CH2:42]Br>CN(C)C=O>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([CH2:42][CH2:41][O:40][CH3:39])[CH2:9]2)=[N:16][CH:17]=1
Reactant: COCCBr
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(CCOC)C2)ncc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.4 %

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (30 mg, 0.0667 mmol) was placed in dimethylformamide (3 mL) and cesium carbonate (65 mg, 0.200 mmol, 3.0 eq) was added followed by 2-bromoethyl methyl ether (11.2 mg, 0.0804 mmol, 7.6 μL, 1.2 eq). The reaction was stirred at room temperature for 72 hours and was then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 2-{5-chloro-2-[10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a yellow foam (8.25 mg, 24%). LCMS (m/e) 507 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.03 (s, 1H), 8.66 (d, 1H, J=8.0 Hz), 8.08 (s, 1H), 7.50-7.40 (m, 2H), 7.34 (d, 1H, J=2.1 Hz), 7.30-7.20 (m, 1H), 7.10-6.98 (m, 2H), 6.93 (s, 1H), 6.19 (bs, 1H), 3.48 (t, 2H, J=6.0 Hz), 3.33 (s, 3H), 3.03 (d, 3H, J=4.9 Hz), 3.0-2.93 (m, 3H), 2.92-2.86 (m, 1H), 2.61 (t, 2H, J=6.0 Hz), 2.35-2.26 (m, 2H), 2.24-2.17 (m, 2H), 1.63-1.57 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:16])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([O:13]CC)=[O:12].Cl>[Li+].[OH-]>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:16])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1c(C)[nH]c2c1CCCC2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Temperature: 0 °C
Yield: 73.6 %

Procedure:
ethyl 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (S3) 1.0 g (4.5 mmol) in 25 ml aq. LiOH solution (1 mol/L) was stirred for 48 hours at 70° C. The mixture was poured into the ice water, then acidified with 6 mol/L HCl to pH 1 to 2. The gray solid was collected by filtration, washed with water and dried in vacuum condition to give 0.64 g (74%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:24]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:34])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:34][C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][N:29]=4)[N:24]=[CH:25][CH:26]=3)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)Cl)cc2)[C@H]1c1ccccc1
Reactant: Nc1ccnc2cccnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC(=O)N(c2ccc(C(=O)Nc3ccnc4cccnc34)cc2)[C@H]1c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a vessel charged with (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoyl chloride (50 mg, 0.152 mmol) were added DCM (606 μL), 1,5-naphthyridin-4-amine (commercially available from Astatech Inc., Bristol, Pa.) (24 mg, 0.167 mmol), and DIEA (55.6 μL, 0.318 mmol) respectively. The vessel was sealed and shaken overnight at 40° C. The mixture was dried under reduced pressure and purified using a 25 g, 15 m spherical silica column (Interchim) ramping 0-100% EtOAc in heptane from 0-100% to elute product, which was lyophilized from MeOH/H2O to yield (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-N-(1,5-naphthyridin-4-yl)benzamide (64 mg, 96%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.63 (s, 1H), 9.01 (dd, J=1.6, 4.2 Hz, 1H), 8.93 (d, J=5.0 Hz, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.46 (dd, J=1.6, 8.5 Hz, 1H), 8.01-7.96 (m, 2H), 7.89 (dd, J=4.3, 8.6 Hz, 1H), 7.76-7.70 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.22 (m, 3H), 5.57 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 439.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][NH2:27])=[CH:16]1.C(OCC)(=O)C>CS(C)=O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][NH:27][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=2[NH2:14])=[CH:16]1
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Reactant: NCCCc1c[nH]c2ccccc12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1c(OCCNCCCc2c[nH]c3ccccc23)cccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 68.3 %

Procedure:
A solution containing 2-(2-chloro-ethoxy)-6-nitro-phenylamine (4.1 g, 19 mmol) and 3-(1H-indol-3-yl)-propylamine (7.1 g, 40.8 mmol) in anhydrous dimethylsulfoxide (50 ml) was heated at 60° C. for 12 hours. Ethyl acetate (200 ml) was added and the mixture was washed with saturated sodium bicarbonate (3×200 ml) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. Purification by chromatography (ethyl acetate:hexanes:2N ammonia methanol=25:25:1) afforded 4.6 g (68.9%) of the product as a yellowish red viscous oil; MS EI m/e 354 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:23][CH2:24][Cl:25])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCCOc1ccc(-c2ccc(Br)cc2)cc1
Yield: 97.9 %

Procedure:
Following the procedure described in example 1§E, but starting from 4-bromo-4′-hydroxybiphenyl (5 g), potassium carbonate (13.8 g) and 1-bromo-3-chloropropane (15.7 g) in acetonitrile (100 mL) affords 6.4 g of 4′-bromo-4-(3-chloropropoxy)biphenyl as white crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH3:14][C:8]([CH:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][O:6]1)([CH3:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(C)(C)C1CCC(O)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)C1CCC(=O)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
To a stirred solution of methyl 2-(5-hydroxytetrahydro-2H-pyran-2-yl)-2-methylpropanoate (187 mg, 0.925 mmol) in DCM (5 mL) containing 4 Å molecular seives (˜250 mg) was added PCC (259 mg, 1.202 mmol). The reaction mixture was stirred at rt for 3 h, then loaded onto a silica gel column and eluted with 10-20% EtOAc in DCM to afford methyl 2-methyl-2-(5-oxotetrahydro-2H-pyran-2-yl)propanoate as a clear oil (105 mg). 1H NMR (400 MHz, CDCl3) δ ppm 4.18 (1H, dd, J=16.56, 1.76 Hz), 3.87-4.01 (2H, m), 3.73 (3H, s), 2.59-2.69 (1H, m), 2.48 (1H, dt, J=17.13, 8.63 Hz), 1.93-2.04 (2H, m), 1.27 (3H, s), 1.15-1.24 (3H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].CS(O[CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)(=O)=O>>[NH2:24][CH2:23][CH2:22][N:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:8]=2)[C:6]#[N:7])=[N:16]1
Reactant: N#Cc1cc(-c2ccn[nH]2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Product: N#Cc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 2-nitro-5-(1H-pyrazol-5-yl)benzonitrile (1.00 g) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (1.45 g) using the method of Example 37(c). Yield 0.32 g (as HCl-salt). 1H-NMR (400 MHz; d6-DMSO): δ 3.34 (t, 2H), 4.50 (t, 2H), 7.15 (d, 1H), 7.99 (d, 1H), 8.21 (br s, 2H), 8.39 (dd, 1H), 8.45 (d, 1H), 8.61 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12]C(=O)OCC3C=CC=CC=3)[CH:11]=1)[O:8][CH2:7][CH2:6][CH2:5]2>C(O)C.[Pd]>[NH2:12][C:10]1[CH:11]=[C:2]([F:1])[CH:3]=[C:4]2[C:9]=1[O:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=C(Nc1cc(F)cc2c1OCCC2)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)cc2c1OCCC2

Procedure:
8.1 g of the compound obtained in Step 3 are dissolved in 80 ml of ethanol. The solution is hydrogenated at normal pressure and room temperature in the presence of 0.39 g of palladium-on-carbon. Filtration and evaporation yield 4.6 g of a liquid which corresponds to the expected product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([O-:12])=[O:11].[Na]>CS(C)=O>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: CCCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc([N+](=O)[O-])cc1
Yield: 30 %

Procedure:
1-bromooctane (1 g, 5.18 mmole) and 4-nitrophenol, sodium salt (0.92 g, 5.71 mmole) were refluxed in DMSO (30 ml) at 120° C. for 5 hours. The DMSO was distilled off to near dryness. The resulting brown residue was loaded onto a silica column and eluted with 10:1 mixture of petroleum ether and diethylether. The yield was 30%. 1H NMR (CDCl3, peaks at =8.18 (m, 2H), 6.93 (m, 2H), 4.04 (t, 2H), 1.81 (p, 2H), 1.33 (m, 10H), 0.89 (t, 3H)). Elemental analysis calculated for C14H21O3N: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.97; H, 8.34; N, 5.52.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[CH:15][CH:16]=[C:4]2[N:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:17][C:16]1[CH:15]=[N:14][N:5]2[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: Clc1cc(N2CCOCC2)n2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(N2CCOCC2)n2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
There was dissolved, in methylene chloride (2 mL), 5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (100 mg, 0.419 mM), then N-bromo-succinimide (78.8 mg, 0.443 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was diluted with a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off. The resulting residue was purified by the silica gel column chromatography (methylene chloride) to thus give the title compound (80.7 mg, yield: 61%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][CH:10]([OH:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:12][CH:10]([CH3:11])[CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1
Reactant: O=Cc1cn[nH]c1
Reactant: CC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(O)Cn1cc(C=O)cn1
Temperature: 150 °C

Procedure:
Combine 1H-pyrazole-4-carbaldehyde (0.150 g, 1.56 mmol), racemic 1-bromo-2-propanol (0.260 g, 1.87 mmol), and potassium carbonate (0.323 g, 2.34 mmol) in acetonitrile (2 mL). Heat in microwave at 150° C. for 20 min. Filter, wash with acetonitrile and concentrate filtrate. Purify via silica gel chromatography, eluting with 0:100 to 100:0 ethyl acetate:hexanes) to give the title preparation (177 mg, 73%). GC-MS: m/z=154 [M+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(F)cc1Br
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ccc(F)cc1Br
Reaction time: 2 h

Procedure:
A solution of 10.9 g. (0.05 mole) of 2-bromo-4-fluorobenzamide in 50 ml. of dry pyridine is stirred and cooled in an ice-bath while 11.2 g. (0.0525 mole) of trifluoroacetic anhydride is added dropwise. After 2 hours at room temperature, the bulk of the solvent is evaporated under reduced pressure and the residue is dissolved in ether. Evaporation of the washed and dried ethereal extract under reduced pressure leaves the product as the residual solid. Sublimation at 55°C. and 0.05 mm. yields white crystals, m.p. 75°-76.5°C. A sample from a previous experiment was resublimed for analysis, m.p. 77°-78°C.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][CH:6]1[C:7]([CH2:16][O:17][CH3:18])=[CH:8][C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3].I[CH3:20].[Al]>C(#N)C.[Ag]=O>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][CH:6]1[C:7]([CH2:16][O:17][CH3:18])=[CH:8][C@H:9]2[CH2:14][O:15][CH3:20])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2CC1C(COC)=C[C@H]2CO
Reactant: CI
Agent: O=[Ag]
Agent: [Al]
Solvent: CC#N
Product: C=CCON1C(=O)N2CC1C(COC)=C[C@H]2COC
Yield: 31.6 %

Procedure:
To a stirred solution of Intermediate 123 (0.3 g, 1.18 mmol) in ACN (12 mL) was added iodomethane (0.734 mL, 11.80 mmol) and silver oxide (1.094 g, 4.72 mmol). The reaction was stirred at rt with aluminum foil wrapped around overnight. LCMS showed product. The mixture was filtered and concentrated. The residue was then purified by silica gel column (40 g, 0-100% Hex/EA) to afford the title compound (0.100 g, 31.6%) as an oil.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:4]12[CH2:5][CH:1]([CH:2]=[CH:3]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]2=1
Reactant: O=S(=O)(Oc1ncccc1CC1CC=CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C1=CC2CC1Cc1cccnc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
Trifluoro-methanesulfonic acid 3-cyclopent-3-enylmethyl-pyridin-2-yl ester (3.1 g, 10.1 mmol) was stirred in DMF (20 mL) and degassed (3 N2/vacuum cycles) then treated under a N2 atmosphere with triethylamine (1.52 g, 15 mmol), 1,3-bis(diphenylphosphino)propane (334 mg, 0.80 mmol) and palladium acetate (72 mg, 0.32 mmol). After 20 min. the mixture was warmed to 100° C. under nitrogen for 18 h, at which time the reaction was deemed 90% complete. Additional triethylamine (1 mL, 7.2 mmol) was added and the mixture brought to 110° C. for 6 h at which time TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled and poured into 50% saturated aqueous NaCl solution (75 mL) then extracted with EtOAc (4×30 mL). The combined organic layer was washed with H2O (2×50 mL), saturated aqueous NaHCO3 solution (50 mL), saturated aqueous NaCl solution (50 mL), dried over Na2SO4, filtered and concentrated to an oil, 2.3 g. Of this material 1.89 g was chromatographed on silica gel eluting with 20% EtOAc/hexanes to provide an oil (1.07 g, 77%). (TLC 20% EtOAc/hexanes Rf 0.21); 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J=4.9, 0.7 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 6.92 (dd, J=7.5, 4.9 Hz, 1H), 6.21 (dd, J=5.5, 2.9 Hz, 1H), 5.73 (dd, J=5.5, 2.6 Hz, 1H), 3.43 (m, 1H), 2.86 (m, 2H), 2.40 (d, J=16.2 Hz, 1H), 2.21 (m, 1H), 1.80 (d, J=10.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.0, 145.0, 138.2, 138.0, 131.7, 130.1, 121.6, 47.3, 39.5, 37.9, 29.7; APCl MS m/z 158.1 (M)+.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH2:11]([CH:13]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH3:34])[CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:35])[CH:20]=2)[N:15]2[CH:36]=[CH:37][CH:38]=[C:14]12)[CH3:12].O>C(Cl)Cl>[CH2:11]([CH:13]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH3:34])[CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:35])[CH:20]=2)[N:15]2[C:36]([CH:4]=[O:5])=[CH:37][CH:38]=[C:14]12)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCC1c2cccn2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC1c2ccc(C=O)n2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 25 ml round bottom flask under nitrogen charged with 10 ml of methylene chloride was added 0.1 ml (1.25 mmol) of DMF and cooled to 0° C. Added 0.12 ml of phosphorous oxychloride and stirred for 15 minutes. 0.40 g (1 mmol) of the product from Example 18 was added and the mixture was stirred at room temperature for 16 hours. At the end of this time added 5 ml of water and stirred vigorously an additional 0.5 hr. The solution was diluted with methylene chloride and the layers separated. The aqueous phase was extracted with methylene chloride and combined with the previous layer. After drying (MgSO4) and concentrating the crude solid was subjected to column chromatography on silica gel, eluting with 30% ethyl acetate:hexane. The product was collected and briefly characterized, then used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[N+:27]([O-])=O)(=[O:16])=[O:15])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.O.NN>[Ni]>[NH2:27][C:18]1[CH:19]=[C:20]([C:23]([F:25])([F:24])[F:26])[CH:21]=[CH:22][C:17]=1[S:14]([NH:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2)(=[O:15])=[O:16]
Reactant: COc1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c2ncccc2c1
Agent: [Ni]
Agent: NN
Solvent: O
Product: COc1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2N)c2ncccc2c1
Yield: 58.9 %

Procedure:
In a similar fashion using route 6 general procedure 14, N-(6-methoxyquinolin-8-yl)-2-nitro-4-(trifluoromethyl)benzenesulfonamide (Intermediate 154) (200 mg, 0.47 mmol), Raney nickel (40 mg, 20% wt), hydrazine hydrate (70 μl, 1.41 mmol) gave the title compound (110 mg, 59%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=O)=[CH:20][N:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1COCC1.[ClH:33]>C1COCC1>[ClH:33].[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:19]=[CH:20][C:21]([CH2:22][NH2:24])=[CH:25][CH:26]=4)[CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:19]=[CH:20][C:21]([CH2:22][NH2:24])=[CH:25][CH:26]=4)[CH:13]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
Into a solution of 6-(2-Phenylchroman-6-yloxy) nicotinamide (100 mg) in dry THF (2.0 ml) was added dropwise a solution of borane-THF complex (0.6 ml, 1.0 M in THF). The resulting mixture was refluxed for 4 hours. After cooling to the room temperature 3 M HCl solution was added and THE was evaporated in vacuum. The mixture was made alkaline with 50% NaOH-solution and extracted with ethyl acetate and dried. The hydrochloride of C-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methylamine was obtained via treatment with HCL-ether solution. 1H NMR (400 MHz, d6-DMSO) δ: 8.29 (bs, 3H), 8.21 (s, 1H), 7.95 (d, 1H, J 8.5 Hz), 7.47-7.34 (m, 5H), 7.03 (d, 1H, J 8.5 Hz), 6.89-6.86 (m, 3H), 5.13 (d, 1H, J 8.4 Hz), 4.00 (m, 2H), 2.94 (m, 1H), 2.70 (m, 1H), 2.19 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[H-].[Na+].CS([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:35][C@@H:34]([C:36]3[CH:47]=[CH:46][C:39]4[O:40][C:41]([CH3:45])([CH3:44])[O:42][CH2:43][C:38]=4[CH:37]=3)[O:33][C:32]2=[O:48])=[CH:25][CH:24]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:44][C:41]1([CH3:45])[O:40][C:39]2[CH:46]=[CH:47][C:36]([C@H:34]3[O:33][C:32](=[O:48])[N:31]([CH2:30][CH2:29][C:26]4[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][O:19][CH2:11][C:8]5[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=5)=[CH:24][CH:25]=4)[CH2:35]3)=[CH:37][C:38]=2[CH2:43][O:42]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Reactant: CC(C)Oc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)cc1
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of (4-isopropoxyphenyl)methanol (93 mg) in DMF (2 ml) was treated with sodium hydride (27 mg) under nitrogen and stirred for 0.5 h. To this was added the 2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl methanesulfonate (357 mg) {Example 15 i)} and the resulting solution was stirred for 18 h under nitrogen. The solution was then diluted in EtOAc, washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 40 g) eluting with 40-60° C. petroleum ether-EtOAc (2:1) to give the title compound (156 mg). LCMS RT=3.76 min.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][N:22]=[CH:21][C:20]=4Br)=[N:13][C:12]=3[C:11]([O:27][CH3:28])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34].COCCNC1C=C(C=CN=1)C(NC1SC2C(N3CCOCC3)=CC=C(OC)C=2N=1)=O>>[O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][N:22]=[C:21]([N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH3:34])[CH:20]=4)=[N:13][C:12]=3[C:11]([O:27][CH3:28])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CNCCOC
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccncc3Br)nc12
Agent: COCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Product: COCCN(C)c1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)ccn1

Procedure:
N-(7-[1,4]Dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-bromo-isonicotinamide and N-(2-methoxyethyl)-methylamine were reacted as described for 2-(2-methoxy-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown solid. MS: m/e=473(M+H+).