Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.[CH3:40]C1C=CC=CC=1B(O)O>C(Cl)Cl.CO>[CH3:37][S:34]([CH2:33][CH2:32][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH3:40])(=[O:35])=[O:36]
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1NCCS(C)(=O)=O

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine (example 158, intermediate b) and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of CH2Cl2: methanol (100:0 to 85:15) for the chromatographic purification. Brown oil (85%). MS (ESI): m/z=291.12 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[S:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[N:29](C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[S:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:29])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-2-methyl-benzoic acid (1.65 g) was suspended in dichloromethane (16 mL). A catalytic amount of N,N-dimethylformamide (“DMF”) and oxalyl chloride (1.2 eq.) were added to the suspension. The reaction mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was concentrated and the residue dissolved in dry tetrahydrofuran (16 mL). To the solution was added a solution of ammonium hydroxide (8 mL, 25%). The reaction mixture was stirred at ambient temperature for two hours. It was then quenched by addition of water and extracted with ethyl acetate. The organic extract was washed with a saturated solution of sodium hydrogenocarbonate, dried over magnesium sulfate and concentrated in vacuo. The crude residue was triturated with tert-butylmethylether then the precipitate was filtered and dried under vacuo to give the title compound (841 mg) as a solid. 1H-NMR (CDCl3, 400 MHz): δ=7.50-7.61 (m, 2 H), 7.39-7.50 (m, 1 H), 7.29-7.39 (m, 1 H), 7.14-7.27 (m, 2 H), 6.40 (br. s., 1 H), 6.05 (br. s., 1 H), 4.16 (m, J=17.4, 1 H), 3.74-3.91 (m, 1 H), 2.44-2.49 (m, 3 H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[H-].[Na+].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C)C=O>[C:15]([Si:12]([CH3:14])([CH3:13])[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1cnc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1CCc2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a 0° C. solution of 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (24.0 g, 200 mmol) in N,N-dimethylformamide (68 mL) was added a 60% dispersion of sodium hydride in mineral oil (12.0 g, 300 mmol) portionwise. The mixture was stirred at 0° C. for 30 min and then a solution of tert-butyldimethylsilyl chloride (46 g, 300 mmol) in N,N-dimethylformamide (100 mL) was added to the above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 3 h and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 5% ethyl acetate/hexanes) to afford 1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (31 g, 66%) as a yellow oil: LC/MS m/e calcd for C13H23N2Si [M+H]+ 235.42, observed 235.3; 1H NMR (400 MHz, CDCl3) δ ppm 0.35 (s, 6H), 0.98 (s, 9H, 3×CH3), 3.02 (t, J=8.6 Hz, 2H), 3.68 (t, J=8.6 Hz, 2H), 6.40 (dd, J=5.2 Hz, 7.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.80 (d, J=5.2 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=3)[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=3)[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4Cc4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(COc2ccc3cc(-c4ccc(-c5ccccc5)n4Cc4ccc(C(F)(F)F)cc4)ccc3c2)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of methyl 4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoate (200 mg, 0.338 mmol), prepared in the previous step, and 1 N NaOH (507 μL, 0.507 mmol) in 20 mL of THF plus 20 mL of methanol plus 5 mL water was refluxed under nitrogen for 9 h. The reaction was filtered and then allowed to cool to room temperature. The reaction was acidified by the addition of 2.5 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The residue was diluted with water. The solid formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (186 mg, 95%) as an off-white solid, mp 228–229° C. Elemental Analysis for C36H26F3NO3.0.15 H2O.0.04 C4H8O Calc'd: C, 74.47; H, 4.60; N, 2.40. Found: C, 74.52; H, 4.49; N, 2.68.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH3:15])[CH2:12][N:11]([C:27](Cl)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH:37]12[CH2:43][CH:40]([NH:41][CH2:42]1)[CH2:39][O:38]2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=3)[CH3:15])[CH2:12][N:11]([C:27]([N:41]3[CH2:42][CH:37]4[CH2:43][CH:40]3[CH2:39][O:38]4)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: C1OC2CNC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)N2CC3CC2CO3)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a stirred solution of (3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(SR)-1-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-pyrrolidine-1-carbonyl chloride (30 mg, 0.064 mmol) in CH2Cl2 (3 mL) were added Et3N (0.015 mL, 0.11 mmol) and 2-Oxa-5-aza-bicyclo[2.2.1]heptane (commercially available) (7 mg, 0.070 mmol). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, EtOAc) to yield 27 mg the title compound as a white solid. ES-MS m/e: 530.1 (M+H+).
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([OH:9])[CH2:2]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>ClCCl>[C:17]([O:9][CH:3]1[CH:4]2[CH:5]([O:6][CH2:7][CH2:8]2)[O:1][CH2:2]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: OC1COC2OCCC12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1COC2OCCC12
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Hexahydrofuro[2,3-b]furan-3-ol (IV, 60 g) was dissolved in dichloromethane (300 mL) and cooled to 0-5° C. To the cooled solution triethylamine (58.2 g), N,N-dimethylaminopyridine (1.12 g) was added, acetic anhydride (56.5 g) was added for 30-60 minutes at the same temperature, the mass temperature was raised to 25-35° C. and stirred for 2-4 hours. After completion of reaction the mass was cooled to 10-20° C., water (120 mL) was added, stirred for 30 minutes, separated the organic layer, washed with 10% sodium chloride solution (120 mL) and distilled out dichloromethane to get title compound (yield 72 g). Further, the product was purified by fractional distillation to get pure Hexahydrofuro[2,3-b]furan-3-yl acetate III (yield 54 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(OC(F)(F)F)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(OC(F)(F)F)cc1CBr
Yield: 70 %

Procedure:
To a solution of 2-methyl-4-trifluoromethoxy-benzonitrile 15 (1.3 g, 6.5 mmol) in carbon tetrachloride (25 mL) was added N-bromosuccinimide (1.7 g, 9.7 mmol) and 2,2′-azobisisobutyronitrile (cat.). The reaction mixture was refluxed 6 hrs, filtered, concentrated, and partitioned between ether and water. The ether layer was dried, concentrated, and purified by silica gel chromatography (10% ether/hexanes) to yield a clear oil (70%). 1H NMR (400 MHz,CDCl3) δ7.73 (d, J=8.4 Hz, 1 H, Ar), 7.41 (s, 1 H, Ar), 7.27 (d, J=8.4 Hz, 19 H, Ar), 4.61 (s, 2 H, CH2).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[CH2:18][CH2:19][NH2:20].Cl>CO.CCOCC>[OH:7][CH2:8][CH2:9][C:10]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=1[CH2:18][CH2:19][NH2:20]
Reactant: NCCc1ccc(Cl)c(Cl)c1CCOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCCc1ccc(Cl)c(Cl)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
81 g of the product obtained above according to (b) are dissolved in 38 ml of methanol. 80 ml of a saturated solution of hydrogen chloride in ether are added, the temperature being kept between 20° and 25° C. The mixture is stirred for 30 minutes at room temperature and then concentrated to dryness. The residue is dissolved in 250 ml of water, washed twice with ethyl ether, rendered alkaline with a solution of NaOH and extracted with CH2Cl2. After drying over MgSO4, the extract is concentrated to dryness, the residue is taken up in 800 ml of isopropyl ether, an insoluble material is filtered off on Celite, the filtrate is concentrated under vacuum to about 300 ml and seeded with crystals of amino alcohol and the mixture is stirred overnight. The crystals are filtered off and rinsed with isopropyl ether and then with n-pentane to give 30.2 g of the expected product. M.p. =90°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:35][CH2:34][C@@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH2:36][CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C[C@H](N)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.226 mmol), (S)-2-amino-4-methylpentan-1-ol (28 mg, 0.24 mmol), and HATU (90 mg, 0.24 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.13 mL, 0.77 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated to afford 73 mg (59%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide as a white solid. MS: [M+H]+=541.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][O:17]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:11]2[CH2:16][CH2:15][C:14]3([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][O:17]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: Clc1nccc(I)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1nccc(N2CCC3(CC2)OCc2ccccc23)c1Cl
Temperature: 110 °C

Procedure:
A mixture of D10 (1 g, 3.655 mmol), spiro[isobenzofuran-1(3H),4′-piperidine], hydrochloride [CAS 37663-44-8] (0.83 g, 4.386 mmol) and DIPEA (1.273 ml, 7.309 mmol) in CH3CN (9 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution) and extrated with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D21 (0.199 g, 16%) as a white solid. M.P. 160.8° C.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:5].CC(C)([O-:19])C.[K+].O>CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:19])=[O:5]
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1ccccn1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-(trans)-2-pyridin-2-yl-cyclopropanecarboxylic acid methoxy-methyl-amide (950 mg, 4.61 mmol, 1 eq) in Et2O (30 mL), potassium tert-butoxide (569 mg, 5.07 mmol, 1.1 eq) and H2O (0.4 mL) were added. The mixture was stirred at r.t. for 18 hours. Potassium tert-butoxide (1.86 g, 16.6 mmol, 3.6 eq.) was added again. The mixture was stirred at r.t. for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (5 mL) and formic acid (3 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@@H:13]([NH2:15])[CH3:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C@@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[C:34]([F:35])=[CH:33][N:32]=[C:31](F)[N:30]=1)[CH3:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>CS(C)=O.CCOC(C)=O>[C:16]([O:20][C@@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[C:34]([F:35])=[CH:33][N:32]=[C:31]([NH:15][CH:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][N:10]=2)[CH3:14])[N:30]=1)[CH3:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@H](N)c1ncc(-c2ccc(Cl)cc2)o1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ncc(-c2ccc(Cl)cc2)o1
Temperature: 120 °C
Yield: 73 %

Procedure:
To a solution of (S)-1-(5-(4-chlorophenyl)oxazol-2-yl)ethanamine 75 mg, 0.337 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (101 mg, 0.337 mmol) in DMSO (1 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.118 mL, 0.674 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (25 ml), wash with water (25 ml), brine (25 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-10% EtOAc/DCM afforded 124 mg yellow foam: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.8 Hz, 1H), 7.61-7.49 (m, 2H), 7.45-7.36 (m, 2H), 7.28 (d, J=6.2 Hz, 1H), 5.65 (d, J=8.9 Hz, 1H), 5.43-5.27 (m, 1H), 4.69 (qd, J=5.6, 2.9 Hz, 1H), 4.62-4.35 (m, 2H), 4.23-4.01 (m, 1H), 1.68 (d, J=12.8 Hz, 2H), 1.26-1.16 (m, 2H), 1.12 (s, 8H), 1.05 (d, J=6.4 Hz, 3H). HRMS(C) tR=1.55 min; m/z 503.1736
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22]2)=[CH:17][CH:16]=1.C([O-])(O)=[O:29].[Na+].O>C1COCC1.C(Cl)Cl>[O:27]=[C:24]1[CH:23]=[CH:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:2]([C:3]3[NH:7][C:6]4[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=4[N:4]=3)=[O:29])=[CH:16][CH:17]=2)[CH:26]=[CH:25]1
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Reactant: O=C([O-])O
Reactant: Nc1ccc(-n2ccc(=O)cc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(-n2ccc(=O)cc2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 769 mg 2-Trichloromethyl-1H-benzoimidazole in 10 mL THF were slowly added to a mixture containing 304 mg 1-(4-Amino-phenyl)-1H-pyridin-4-one, 1.3 g NaHCO3, 40 mL THF and 15 mL H2O. The mixture was stirred vigorously for 3 h at room temperature, diluted with 200 mL CH2Cl2 and washed with 40 mL of a saturated NaHCO3-solution. The aqueous solution was extracted with CH2Cl2 (3×200 ml) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give a brown solid, which was pure enough for the following reactions.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[C:31]([Cl:34])(=[O:33])[CH3:32]>C(Cl)Cl>[ClH:34].[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:31](=[O:33])[CH3:32])[CH:22]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:30]
Reactant: CCCN1CCC(N(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCCN1CCC(N(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC(C)=O)c2)CC1
Product: Cl
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 0.96 g (2.3 mmol) of N,N-diethyl-4-[3-hydroxyphenyl(1-propylpiperidin-4-yl)amino]benzamide was stirred in 20 mL of CH2Cl2 and 0.17 mL of acetyl chloride was added. The mixture was stirred for 2 h. The solvent was evaporated and the residue recrystallized from 2-PrOH to give 0.7 g (62% yield) of the title compound as a white crystalline solid: mp 218-219° C. MS m/z=452 (M++H). 300 MHz 1H NMR (DMSO-d6) δ7.3 (d 2H); 7.2 (m, 1H);6.9 (d, 2H);6.7 (m, 2H);4.1 (t, 3H); 3.6 (d, 2H); 3.4 (m, 4H); 2.8 (m, 4H); 2.4(m, 2H); 2.2(s, 3H) 2.1 (d, 2H); 1.9 (m, 2H); 1.2 (t, 6H), 1.0 (t, 3H). Anal calcd. for C27H37N3O3.HCl: C, 66.45; H, 7.45; N, 8.61. Found: C, 66.07; H, 7.83; N, 8.32.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([Cl:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[ClH:26].[CH2:19]([S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: c1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and benzyl chloride (0.184 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 128 mg of the product 201. 1H NMR (DMSO-d6) δ 11.30 (s, 2H), 7.70-7.50 (m, 2 H), 7.50-7.35 (m, 3 H), 7.20-6.95 (m, 6 H), 6.90-6.70 (m, 4 H), 5.78 (s, 2H), 4.90 (s, 2 H); MS: m/z 345 (M++1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25](C)([CH3:27])C(C)(C)[O:23]2)=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31](C)([O-:33])=[O:32].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:27][N+:31]([O-:33])=[O:32])[C:15]=2[CH:18]=[CH:19][C:20]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)c(B2OC(C)(C)C(C)(C)O2)c1OCCCOCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1OCCCOCc1ccccc1)B(O)OC2C[N+](=O)[O-]

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (1.14 g, 2.78 mmol), nitromethane (0.45 mL, 8.34 mmol), NaOH (0.78 g, 1.95 mmol), THF (3 mL) and water (9 mL). Purification: flash column chromatography (25% EtOAc/hexanes): yield 0.42 g (41%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.41 (s, 1H), 7.37-7.18 (m, 6H), 7.03 (d, J=7.8 Hz, 1H), 5.69 (dd, J=9.2, 2.5 Hz, 1H), 5.28 (dd, J=13.7, 2.7 Hz, 1H), 4.52 (dd, J=13.3, 9.4 Hz, 1H), 4.46 (s, 2H), 4.33 (t, J=6.1 Hz, 2H), 3.58 (t, J=6.1 Hz, 2H), 2.12 (s, 3H), 2.01-1.87 (m, 2H). MS (ESI): m/z=370 (M−1, negative).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:30][N:31]([CH3:35])[C:32](=[O:33])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 108 %

Procedure:
A suspension of 2.00 g (0.006 mol) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol in 160 ml of toluene was treated with 2 ml (0.014 mol) of triethylamine, 0.88 g (0.007 mol) of 4-dimethylaminopyridine and 0.7 ml (0.007 mol) of dimethylcarbamoyl chloride and then boiled under reflux for 4 hours. After cooling the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. After extraction with methylene chloride and chromatography over silica gel with ethyl acetate/hexane 1:2 there were obtained 2.40 g of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl dimethylcarbamate as an oil.