Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[N+](=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N-].[O:12]=[CH:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18]>C(Cl)Cl>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][C:13](=[O:12])[CH2:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH3:11]
Reactant: CC(=O)OCCC=O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cl[Sn]Cl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCOC(C)=O
Yield: 31.2 %

Procedure:
Charge a round-bottom flask with tin(II) chloride (16.6 g, 0.088 mol), purge with nitrogen, and add dichloroethane (300 mL) by cannula. Add ethyl diazoacetate (92 mL, 0.88 mol) by cannula and stir 10 min. Add a solution of acetic acid 3-oxo-propyl ester (0.44 mol) in CH2Cl2 (600 mL) slowly by cannula over 1 h, then stir the reaction in a 50° C. oil bath for 3 h. Concentrate under vacuum, add saturated aqueous NaHCO3 and remove the organic phase. Extract the aqueous portion with EtOAc (2×). Wash the combined organic portions with brine, dry over MgSO4, filter through Celite®, and concentrate under vacuum. Purify by flash chromatography on silica gel, eluting with a gradient of EtOAc/hexane 8%-25% to give the title compound (27.8 g, 31%), exact mass 202.08, mass spectrum (ES) 225.1 (M+Na). 1H NMR (CDCl3): δ 4.34 (t, J=6.1 Hz, 2H), 4.20 (q, J=7.1 Hz, 2H), 3.46 (s, 2H), 2.89 (t, J=6.1 Hz, 2H), 2.03 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F:22][C:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC(Cl)=CC=2)[O:28][N:27]=1)([CH3:25])[CH3:24]>CN(C=O)C>[F:22][C:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:21]=[CH:20][CH:19]=[C:4]([O:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=4)[N:9]=[CH:8][N:7]=3)[CH:3]=2)=[O:33])[O:28][N:27]=1)([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1O
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1O
Temperature: 60 °C

Procedure:
To a stirred solution of 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (200 mg, 0.710 mmol) (prepared as described in example 107A, steps 1 through 7) in anhydrous DMF (6 mL), was added 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate described in Example 257A (317 mg, 1.07 mmol) and the mixture was heated to 60° C. for 3 h. Concentration in vacuo followed by trituration of the resulting solid with methanol afforded, after filtration and drying, 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (162 mg, 50%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.30 (s, 1H), 9.08 (s, 1H), 8.50 (s, 1H), 7.53 (dd, J=2.1, 2.1 Hz, 1H), 7.50 (s, 1H), 7.37-7.44 (m, 2H), 7.32 (dd, J=8.4, 1.8 Hz, 1H), 6.97 (dd, J=8.4, 1.8 Hz, 1H), 6.15 (s, 1H), 4.00 (s, 3H), 1.66 (d, J=22 Hz, 6H); LC-MS (ESI) m/z 454 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[CH2:9][F:10])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:11])[CH2:9][F:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CF)c1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CF)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(6-Bromopyridin-2-yl)-2-fluoroethanone (0.53 g, 2.43 mmol) was taken up in MeOH (12 mL) and cooled to 0° C. Sodium borohydride (0.092 g, 2.43 mmol) was added and the mixture stirred at 0° C. for 1 hour. Water was added and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[N:24][OH:25])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NO
Reactant: COc1ccc(C(=O)c2ncc(C(F)(F)F)cc2Cl)cc1Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2ncc(C(F)(F)F)cc2Cl)cc1Br
Yield: 97.7 %

Procedure:
A solution of (3-bromo-4-methoxyphenyl)[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methanone (8.90 g, 22.5 mmol) and hydroxylamine hydrochloride (3.92 g, 56.3 mmol) in pyridine (60 mL) was stirred 2 h at 50° C. then overnight at room temperature. After removal of the solvent in vacuo, addition of water (50 mL) and extraction with ethyl acetate (3×40 mL), the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel to afford 1-(3-bromo-4-methoxyphenyl)-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-hydroxymethanimine [9.00 g, yield 88%; HPLC/MS: m/z=410 (M+H); log P(HCOOH)=3.37].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21](O)=[O:22])=[CH:10][CH:9]=2)=[O:4].O.Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:21][OH:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(CO)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a solution of 2-benzyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid 3-methyl ester (300 mg) in THF (3 ml) was added dropwise a solution (1M, 1.5 ml) of borane complex in THF under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 4 hrs. To the reaction mixture was further added dropwise a solution (1M, 3 ml) of borane complex in THF at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and 10% hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (280 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([OH:18])=O)[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:15])[CH3:14])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][C:21]1[C:22](=[O:31])[NH:23][C:24]([CH3:30])=[CH:25][C:26]=1[CH:27]([CH3:29])[CH3:28].C(O)(C(F)(F)F)=O.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([NH:19][CH2:20][C:21]3[C:22](=[O:31])[NH:23][C:24]([CH3:30])=[CH:25][C:26]=3[CH:27]([CH3:28])[CH3:29])=[O:18])[C:7]3[CH:12]=[N:11][N:10]([CH:13]([CH3:14])[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(C3CC3)nc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 7 from 6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (250 mg, 1.019 mmol), 3-(aminomethyl)-6-methyl-4-(1-methylethyl)-2(1H)-pyridinone.TFA (300 mg, 1.019 mmol), HOAT (208 mg, 1.529 mmol), EDC (293 mg, 1.529 mmol), N-methylmorpholine (0.448 mL, 4.08 mmol), and DMF(6 mL), wherein the reaction time was 48 h. The final product was collected following a basic extraction (to remove residual starting material) as a white solid, 30 mg (7%). LCMS E-S (M+H)=408.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.16 (m, 10 H), 1.38-1.54 (m, 6 H), 2.16 (s 3 H), 2.19-2.30 (m, 1H), 3.12-3.29 (m, 1 H), 4.29-4.48 (m, 2 H), 5.03-5.21 (m, 1 H), 6.03 (s, 1 H), 7.39 (s, 1 H), 8.21 (s, 1 H), 8.63-8.81 (m, 1 H), 11.56 (s, 1 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[CH3:12]/[C:13](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:14]/[C:15](OC)=[O:16].O.[OH-].[Na+]>O1CCCC1.O.C(OCC)C>[CH3:12]/[C:13](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:14]/[CH2:15][OH:16]
Reactant: COC(=O)/C=C(/C)CCC=C(C)C
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCC/C(C)=C\CO
Reaction time: 0.33 h

Procedure:
To 10 ml. of 1 M lithium aluminum hydride in tetrahydrofuran, cooled to 0°, is added, dropwise, 0.28 ml. of 18 M sulfuric acid. The addition should be made at a rate such that the temperature remains at or below about +15°. After the addition is complete, the reaction mixture is stirred for 20 minutes and 0.55 grams of methyl (Z)-3,7-dimethylocta-2,6-dienoate is added. The reaction is allowed to proceed for about 3 hours while keeping the temperature between 0° and +5°. Then 20 ml. of ethyl ether is added, followed successively by 0.4 ml. of water, 0.4 ml. of a 15% sodium hydroxide water solution, and 1.2 ml. of water. The mixture then is filtered and the solid remaining is washed with ethyl ether. The organic filtrate is dried over sodium sulphate, filtered and evaporated under reduced pressure to yield, as an oil, (Z)-3,7-dimethylocta-2,6-dien-1-ol.
Reaction SMILES: CC(O)=O.C1COCC1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].[Br:25]Br>CCOC(C)=O.CCCCCC>[Br:25][CH2:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)=[O:19]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)c(NS(C)(=O)=O)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1F
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a stirred 20° C. solution (4 mL) of 40% HOAc/THF containing 1-[4-fluoro-3-[(methylsulfonyl)amino]phenyl]ethanone (1.0 g, 4.3 mmol) was added bromine (223 mL, 4.3 mmol). After stirring one hour, a second equivalent of bromine was added and the reaction run for 3.5 hours whereupon the reaction was judged complete by TLC (1:1 EtOAc/hexane). After dilution with EtOAc, the organic layer was washed with aq. NaHCO3 and then brine before drying over Na2SO4. After concentration, 0.58 g (44%) of the title compound was isolated after recrystallization from EtOH.
Reaction SMILES: [C:1]([C:9]1C([N+]([O-])=O)=CC(C(OCC)=O)=CC=1O)(=O)[C:2]1C=CC=C[CH:3]=1.C(I)C.[Cl:27][C:28]1[CH:50]=[CH:49][C:31]([C:32]([C:34]2[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][C:35]=2[OH:48])=[O:33])=[CH:30][CH:29]=1.C(I)CCC>>[CH2:9]([O:48][C:35]1[CH:36]=[C:37]([CH:43]=[C:44]([N+:45]([O-:47])=[O:46])[C:34]=1[C:32](=[O:33])[C:31]1[CH:49]=[CH:50][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:38]([OH:40])=[O:39])[CH2:1][CH2:2][CH3:3]
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Solvent: CCCCI
Solvent: CCI
Product: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(Cl)cc1

Procedure:
By replacing in Example 6, step B, ethyl 4-benzoyl-3-hydroxy-5-nitrobenzoate and ethyl iodide with equimolar amounts of ethyl 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoate and n-butyl iodide respectively and following the procedure described, 3-n-butoxy-4-(4'-chlorobenzoyl)-5-nitrobenzoic acid is obtained with a melting point of 180°-182° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:21][CH:20]=1
Reactant: C1=Cc2ccccc2C1
Reactant: COc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.68 g (20 mmole) of para-methoxy iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with cold ethanol and dried under vacuum to obtain 2.23 g (50%) of 2-(4-methoxy-phenyl)-indene.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:69])[CH2:66][CH2:67][NH2:68]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:68][CH2:67][CH2:66][N:65]([CH3:69])[CH3:64])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 28)(50 mg, 0.124 mmol) and HATU (56.7 mg, 0.149 mmol) was added DMF (2 mL) and the resulting mixture was treated with DIPEA (0.065 mL, 0.373 mmol) then after 5 min with N1,N1-dimethylethane-1,2-diamine (21.90 mg, 0.248 mmol. The resulting solution was stirred at room temperature for 30 min then partitioned between EtOAc and saturated NaHCO3. The organic phase was separated and aqueous layer extracted with EtOAc (×2). The combined organic layers were washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo. The residue divided into 2 portions and each was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and concentrated again, then co-evaporated with toluene. The residue were then dissolved in 1,4-dioxane (2 mL) and treated with hydrogen chloride in 1,4-dioxane (4N, 0.5 mL). After 2 min the solvent was evaporated in vacuo and the precipitate formed triturated with Et2O then dried under house vacuum to give 6-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)nicotinamide, as the d-hydrochloride salt (37 mg, 0.068 mmol, 54.6% yield) as a yellow solid. LCMS (HpH, 2 min), Rt=0.81 min, MH+=473.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][NH2:34])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][NH:34][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc21
Yield: 69.2 %

Procedure:
(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester (290 mg) was prepared by following General Procedure F using 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (300 mg), (2-amino-ethyl)-carbamic acid tert-butyl ester (147 mg), HBTU (380 mg), and DIEA (219 uL).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)[CH3:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(=O)=O>CO>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@@H:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)[CH3:15])[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(c2ncc(F)cn2)CC1
Agent: O=C=O
Solvent: CO
Product: C[C@H](Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(c2ncc(F)cn2)CC1

Procedure:
The racemic 5-fluoro-2-{4-[1-({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)ethyl]-1-piperidinyl}pyrimidine (prepared as in Example 153) was subjected to Chiral HPLC [column: OJ-H, column mobile phase: 70% CO2: 30% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as an off-white solid with Tr of 21.34 min (first eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [N:1]([O-])=O.[Na+].CS(NC1C=CC(N)=CC=1)(=O)=O.Cl.O[C:19]1[C:24](N)=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[S:29]([OH:32])(=[O:31])=[O:30].C1(C=CC=C(O)C=1)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:19]1[CH:24]=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[S:29]([OH:32])(=[O:31])=[O:30]
Reactant: O=N[O-]
Reactant: Nc1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1O
Agent: CS(=O)(=O)Nc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O

Procedure:
An aqueous solution of 7 parts of sodium nitrite is added to 18.6 parts of 4-methylsulfonylaminoaniline in 50 parts by volume of 5N hydrochloric acid at 0°-5° C. The diazo solution is then poured into a stirred suspension, in 1,000 parts of water, of the coupling product obtained by diazotizing 23.4 parts of 2-hydroxy-3-amino-5-nitrobenzenesulfonic acid in a conventional manner and coupling the product to 11 parts of resorcinol in a medium rendered alkaline with sodium carbonate. After the addition, the pH is increased to 9, and the mixture is stirred until coupling is complete. A diazo solution obtained from 21.8 parts of 2-amino-5-nitrobenzenesulfonic acid in a conventional manner is then allowed to run into the mixture at pH 9-9.5, and stirring is continued until the coupling is complete. The resulting dye is complexed with 34 parts of iron(III) chloride in a conventional manner, and the iron complex of the compound of the formula ##STR204## is isolated; this product gives lightfast and wetfast dark brown dyeings on leather.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[N:14][N:15](COCC[Si](C)(C)C)[C:7]=2[CH:6]=1.[I:29]Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[C:13]([I:29])=[N:14][NH:15][C:7]=2[CH:6]=1
Reactant: ClI
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1cnn2COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2[nH]nc(I)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.3 %

Procedure:
To a solution of 6-(2,4-difluorophenoxy)-4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,4-dihydro-pyrazolo[4,3-b]pyridin-5-one (118 mg, 0.289 mmol) in chloroform (25 mL) was added iodine monochloride (141 mg, 3 eq) followed by potassium carbonate (200 mg, 5 eq) and the resulting mixture was heated under reflux with stirring (in the dark) for 24 hours. Additional iodine monochloride (large excess) was added and the resulting solution was stirred under reflux for another 16 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane, and washed 2× with an aqueous solution of Na2S2O3(aq) followed by brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the crude product as an oil (97 mg). Purification by Preparative Thin Layer Chromatography eluting with 60% ethyl acetate in hexanes gave the title compound as an off-white powder (12 mg, (M+H)+=462).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[Si]([O:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH2:38][CH2:39][CH:40]2O)(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:40]2[C:41]3[C:37](=[C:36]([OH:35])[CH:44]=[CH:43][CH:42]=3)[CH2:38][CH2:39]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(C2CCc3c(O)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A solution of ethyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (20.0 g, 50.5 mmol), 4-{[tert-butyl(dimethyl)silyl]oxy}indan-1-ol (14.7 g, 55.6 mmol) and triphenylphosphine (14.6 g, 55.6 mmol) in tetrahydrofuran (300 mL) was stirred under ice-cooling, and diethyl azodicarboxylate (40% toluene solution, 25.3 mL, 55.6 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 hr. To the reaction mixture were added reagents (4-{[tert-butyl(dimethyl)silyl]oxy}indan-1-ol, triphenylphosphine and diethyl azodicarboxylate) in a half amount of the above, and the mixture was further stirred for 4 hr. The reaction mixture was concentrated, and diethyl ether and hexane were added to the residue. The resultant insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-hexane/ethyl acetate=30/70) to give a yellow oil. To a solution of the obtained oil in tetrahydrofuran (250 mL) was added tetrabutylammonium fluoride (1 M THF solution, 61.1 mL, 61.1 mmol) under stirring under ice cooling and the mixture was stirred at the same temperature for 3 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30-hexane/ethyl acetate=30/70) to give the title compound (21.5 g, yield 81%, 2 steps) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O-:13].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:13][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: C[O-]
Agent: [K+]
Solvent: CO
Product: COc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 37.9 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (10 g, 51.55 mmol) in methanol (150 ml) at −10° C. a solution of potassium methanolate (3.62 g, 51.55 mmol) in methanol (150 ml) was added over a period of 10 minutes. The mixture was allowed to warm to 0° C. and the solvent was evaporated under reduced pressure at 30° C. The residue was purified by silica gel chromatography with n-heptane/ethyl acetate (3:1) as eluent affording 3.7 g (37.9%) of the title compound. 1.34 g (13.7%) 4-chloro-2-methoxy-5-nitropyrimidine was obtained as a side product