Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCCC1>[N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: NS(=O)(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 7.8 %

Procedure:
Tetrahydrofuran (3 mL) and morpholine (0.68 mL, 7.8 mmol) were added to sulfamide (500 mg, 5.2 mmol) and the mixture was stirred at 100° C. for 4 hours. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=1/0 to 4/1) was performed to give morpholine-4-sulfonamide (Compound FY) (67 mg, yield: 8%).
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[C:29]1([S:43]([OH:46])(=[O:45])=[O:44])[C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:39]([OH:42])(=[O:41])=[O:40])[C:33]=2[CH:32]=[CH:31][CH:30]=1>C(#N)C.CC(C)=O>[C:29]1([S:43]([OH:46])(=[O:45])=[O:44])[C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:39]([OH:42])(=[O:41])=[O:40])[C:33]=2[CH:32]=[CH:31][CH:30]=1.[Cl:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3](=[O:9])[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(CCl)C(=O)C(Br)Oc1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC#N
Solvent: CC(C)=O
Product: CC(C)(CCl)C(=O)C(Oc1ccc(-c2ccc(Cl)cc2)cc1)n1ccnc1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
20.8 g (0.05 mol) of crude 1-bromo-4-chloro-1-[4-(4-chlorophenyl)-phenoxy]-3,3-dimethyl-butan-2-one were dissolved in 120 ml of absolute acetonitrile. 12 g (0.175 mol) of imidazole were added and the mixture was heated for 40 hours under reflux. It was then concentrated by distilling off the solvent in vacuo and the residue was taken up in 300 ml of methylene chloride. The solution was washed three times with 100 ml of water at a time and was dried over sodium sulphate and again concentrated in vacuo. The residue was taken up in 100 ml of acetone and a solution of 9 g (0.038 mol) of 1,5-naphthalenedisulphonic acid in 50 ml of acetone was added. After 2 hours, the precipitate formed was filtered off and dried. 19.6 g (72% of theory) of 4-chloro-1-[4-(4-chlorophenyl)-phenoxy]-3,3-dimethyl-1(imidazol-1-yl)-butan-2-one naphthalene-1,5-disulphonate of melting point 246° C. were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](=[S:17])=S>C(O)C>[CH2:7]([O:6][C:5]([NH:4][CH2:3][CH2:2][NH:1][C:15]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[S:17])=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: S=C=S
Solvent: CCO
Product: O=C(NCCNC(=S)NCCNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a suspension of benzyl 2-aminoethylcarbamate LIX (3 g; 15.45 mmol) in anhydrous ethanol (20 mL) was added carbon disulfide (0.47 mL; 7.73 mmol). The mixture was heated under gently reflux for 22 h. After cooling to r.t., the product precipitated and was filtered, washed with anhydrous ethanol (3×) and air dried. Benzyl N-(2-{[(2-{[(benzyloxy)carbonyl]amino}ethyl)carbamothioyl]amino}ethyl)carbamate LX was obtained as white solid (2.97 g; 6.90 mmol; 89.3% yield). 1H NMR (DMSO-d6) 3.10-3.14 (m, 4H), 3.37-3.42 (m, 4H), 5.00 (s, 4H), 7.30-7.37 (m, 12H), 7.54 (brs, 2H); ESIMS found for C21H26N4O4S m/z 431.4 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1.O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:20][CH2:19][N:18]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: COC(=O)Cl
Reactant: Brc1ccc(C2CCNC2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N1CCC(c2ccc(Br)cc2)C1
Reaction time: 0.08 h
Yield: 111.1 %

Procedure:
Triethylamine (192 mg, 1.9 mmol) was added to a suspension of 3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred for 5 minutes and treated with methyl chloroformate (0.1 g, 1.05 mmol). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give methyl 3-(4-bromophenyl)pyrrolidine-1-carboxylate (0.24 g, quantitative yield) as an oil which was used for next step directly. MS (ES+) 283.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[N:29]12[CH2:37][CH2:36][CH:33]([CH2:34][CH2:35]1)[NH:32][CH2:31][CH2:30]2>C(#N)C>[N:29]12[CH2:37][CH2:36][CH:33]([CH2:34][CH2:35]1)[N:32]([C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[O:8])[CH2:31][CH2:30]2
Reactant: C1CN2CCC(CC2)N1
Reactant: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)NC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1[N+](=O)[O-]
Temperature: 96 °C
Yield: 69 %

Procedure:
To a solution of 5-fluoro-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (Intermediate 2A) (7.39 g, 26.1 mmol) in acetonitrile (240 mL) was added potassium carbonate (14.6 g, 104 mmol) followed by 1,4-diazabicyclo[3.2.2]nonane dihydrochloride (5.45 g, 27.4 mmol). The resulting suspension was heated to reflux at 96° C. overnight. The reaction mixture was filtered and concentrated. Sample was diluted in methanol (100 mL) and split between two 20 g SCX cartridges. Purification by SCX and evaporation to dryness afforded 5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (7.0 g, 18.0 mmol).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:35]([F:38])([F:37])[F:36])=[C:31]([CH:34]=1)[CH:32]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=3[C:35]([F:37])([F:36])[F:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Product: FC(F)(F)c1ccc(Cl)cc1CNc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 5-chloro-2-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 538.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][C:7]=1[CH:8]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH:17]=[CH:18][CH:19]=1)[O:9]2.[Li+].[OH-].Cl>CO>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][C:7]=1[CH:8]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:18][CH:19]=1)[O:9]2
Reactant: CCOC(=O)CCCc1cccc(C2Oc3cccc(OC(F)F)c3-c3ccc(NS(C)(=O)=O)cc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(c1cccc(CCCC(=O)O)c1)Oc1cccc(OC(F)F)c1-2

Procedure:
A solution of Example 115 (110 mg, 0.21 mmol) and aqueous LiOH (1 ml of 10% solution) in methanol (1 ml) was stirred for 3 hours, neutralized with 1M HCl, and extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated. The concentrate was purified by high throughput HPLC with aqueous 0.1% TFA and CH3CN to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=9 Hz, 1H) 6.87-7.56 (m, 10H), 6.24 (s, 1H), 3.00 (s, 1H), 2.55 (t, J=7 Hz, 2H), 2.17 (t, J=7 Hz, 2H), 1.73 (m, J=7 Hz, 2H); MS (ESI(−)Q1MS m/z 502 (M−H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[CH:38][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:28]4=[O:37])[CH2:23][CH2:22]3)=[O:20])=[C:17]([O:40][CH3:41])[CH:16]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[CH:3]([S:4]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[CH:38][C:18]([C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:28]4=[O:37])[CH2:25][CH2:26]3)=[O:20])=[C:17]([O:40][CH3:41])[CH:16]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:5])=[CH2:2]
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cc(OC2CCNCC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(=O)(Cl)Cl
Product: C=CS(=O)(=O)N1CCC(Oc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OC)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL flask containing 3 mL of methylene chloride was added 2-chloro-1-ethanesulfonyl chloride (0.046 mL, 0.44 mmol) and the solution was cooled to 0° C. under N2. To a 10 mL addition funnel containing 8 mL of methylene chloride was added 1-(1-(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (200 mg, 0.4 mmol) from Example 190 and DIEA (0.35 mL, 2.0 mmol). This solution was added slowly over 15 min to the cold, stirred solution of sulfonyl chloride. The reaction mixture was stirred at 0° C. for 30 min and then at ambient temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue purified by pressurized silica gel column chromatography using 95:5 CH2Cl2 :MeOH as eluant. The product-containing fractions were combined and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:19](=[O:21])[CH3:20])[CH:11]=[C:12]([N+:16]([O-])=O)[C:13]=1[O:14][CH3:15].C(=O)([O-])O.[Na+].C(Cl)Cl>C(O)C>[NH2:16][C:12]1[C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=[C:10]([C:19](=[O:21])[CH3:20])[CH:11]=1
Reactant: COc1cc(C(C)=O)cc([N+](=O)[O-])c1OC
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(C)=O)cc(N)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
11.3 g of tin dichloride dihydrate are added to 2.25 g of 3',4'-dimethoxy-5'-nitroacetophenone dissolved in 50 ml of ethanol, whereupon the mixture is stirred at 75° for 30 minutes. Thereupon, the reaction mixture is poured on to 100 g of ice, neutralized with about 300 ml of saturated sodium hydrogen carbonate solution and treated with 150 ml of methylene chloride. The mixture is filtered and the methylene chloride phase is separated. This is dried over sodium sulfate and evaporated, and the residue is recrystallized from ether/petroleum ether. There is obtained 5'-amino-3',4'-dimethoxyacetophenone of m.p. 63°-65°.
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[CH:57]=[C:56]([O:58][C@@H:59]([C@@H:61]2[CH2:65][O:64][C:63]([CH3:67])([CH3:66])[O:62]2)[CH3:60])[N:55]=[C:54]([S:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:71]=2[F:77])[N:53]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:77][C:71]1[C:72]([F:76])=[CH:73][CH:74]=[CH:75][C:70]=1[CH2:69][S:68][C:54]1[N:53]=[C:52]([NH:10][S:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])[CH:57]=[C:56]([O:58][C@@H:59]([C@@H:61]2[CH2:65][O:64][C:63]([CH3:66])([CH3:67])[O:62]2)[CH3:60])[N:55]=1
Reactant: NS(=O)(=O)N1CCOCC1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-morpholine sulfonamide (prepared according to patent WO 2004/011443) (0.15 g), tris(dibenzylideneacetone)dipalladium (0) (55 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (29 mg), cesium carbonate (0.30 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidine (the product of Example 47, step i) (0.25 g) in dioxane (5 ml). The crude material was purified by column chromatography using EtOAc/isohexane (1:9 to 2.5:7.5 gradient) as eluent to give the subtitle compound as an off-white foam Yield: 0.20 g.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:45])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][C:35]([O:43][CH3:44])=[C:36]([O:41][CH3:42])[CH:37]=3)[CH2:32]2)=[CH:25][CH:24]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][N:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][C:35]([O:43][CH3:44])=[C:36]([O:41][CH3:42])[CH:37]=3)[CH2:32]2)=[CH:27][CH:28]=1)=[O:45]
Reactant: COc1cc2c(cc1OC)CN(CCc1ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc34)cc1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(CCc1ccc(Nc3ncnc4ccc(NC(=O)CCN)cc34)cc1)CC2
Yield: 46.1 %

Procedure:
800 mg of [2-(4-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]phenylamino}-quinazolin-6-ylcarbamoyl)-ethyl]-carbamic acid t-butylester dissolved in 16 ml of methylene chloride was reacted with 16 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 200 ml of saturated aqueous sodium bicarbonate solution for 30 mins, filtered under a reduced pressure and dried to obtain the title compound (310 mg, 46%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1.Br[CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:32]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=3)=[CH:12][N:11]=2)=[C:2]([F:1])[C:7]=1[F:8])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCBr
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCC)c(F)c3F)nc2)cn1
Yield: 69 %

Procedure:
The etherification of 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine using 2.7 mmol of 1-bromobutane is carried out analogously to the procedure indicated for Example 3. Corresponding purification gives 0.76 g (69%) of colorless crystals, X 85 SC 156 SA 180 I.
Reaction SMILES: [Cl-].[CH2:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][NH3+:17])[CH3:3].C([O-])([O-])=O.[K+].[K+].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O.[BH4-].[Na+]>CO>[CH2:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][NH:17][CH2:29][C:25]1[O:24][CH:28]=[CH:27][CH:26]=1)[CH3:3]
Reactant: CCc1c(OCC[NH3+])ccc2ccccc12
Reactant: O=Cc1ccco1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: CCc1c(OCCNCc2ccco2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of 1-ethylnaphthalen-2-ol (780 mg, 4.53 mmol) and K2CO3 (626 mg, 4.53 mmol) in 15 mL of acetonitrile was added tert-butyl (2-bromoethyl)carbamate (1.015 g, 4.53 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 7:3) showed the disappearance of 1-ethylnaphthalen-2-ol, solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (5 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {2-[(1-ethylnaphthalen-2-yl)oxy]ethyl}carbamate which was dissolved in 10 mL of 4M HCl in dioxane and stirred for 1 h. The solvent was removed under vacuum and the residue was diluted with n-hexane (20 mL) and triturated at room temperature for 2 h. The solid was filtered and dried under vacuum at 50° C. to afford 2-[(1-ethylnaphthalen-2-yl)oxy]ethanaminium chloride as brown solid (821 mg, 72% yield). To a solution of 2-[(1-ethylnaphthalen-2-yl)oxy]ethanaminium chloride (100 mg, 0.397 mmol) in 10 mL of MeOH, K2CO3 (65 mg, 0.47 mmol) was added. After 10 min, 48 μL (0.58 mmol) of furan-2-carbaldehyde were added. The resulting solution was stirred for 1 h at room temperature, added with sodium borohydride (15 mg, 0.397 mmol) and allowed to stir for further 2 h at room temperature. The solvent was evaporated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 97:3) to afford 2-[(1-ethylnaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine as a brown solid (91 mg, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:10][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[OH:9]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Cl)c(Cl)cc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 4,5-dichloro-2-nitrophenol (15 g, 72 mmol) in acetic acid (150 mL) and water (450 mL), iron powder (16 g, 285 mmol) was added in portions. The resulting mixture was stirred at 50° C. for 2 h. The mixture was allowed to cool to room temperature, filtered, and the cake was rinsed with ethyl acetate. The filtrate was extracted with ethyl acetate. The organic layer was washed with water, NaHCO3 (aq.) and brine, dried over Na2SO4 and concentrated in vacuo to afford the desired product (10 g, 78%).
Reaction SMILES: [N:1]([C@H:4]([C@@H:30]1[CH2:34][C@@H:33]([CH:35]([CH3:37])[CH3:36])[C:32](=[O:38])[O:31]1)[CH2:5][CH:6]([CH:27]([CH3:29])[CH3:28])[C@H:7](OC(=O)C(C)C)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:9]=1)=[N+]=[N-].C(CN)O>C(O)C.[Pd]>[NH2:1][C@H:4]([C@H:30]1[O:31][C:32](=[O:38])[C@H:33]([CH:35]([CH3:37])[CH3:36])[CH2:34]1)[CH2:5][C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:9]=1)[CH:27]([CH3:28])[CH3:29]
Reactant: COCCCOc1cc([C@@H](OC(=O)C(C)C)C(C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1F
Agent: [Pd]
Solvent: NCCO
Solvent: CCO
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1F

Procedure:
A solution of isobutyric acid (S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-1-[4-fluoro-3-(3-methoxy-propoxy)-phenyl]-3-methyl-butyl ester (1.45 g, 2.7 mmol, 1 equiv.), Pd/C (10%, 2.9 g) and ethanolamine (0.17 mL, 2.7 mmol, 1 equiv.) in ethanol (135 mL) were shaken under H2 (1 atmosphere) for 24 hours. The reaction mixture is filtered, before the solvent is evaporated to afford the product as a light grey gum. MS (LC-MS): 424 [M+H]+
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[CH3:13][NH:14][NH2:15]>C(O)C>[OH:6][C:5]1[N:14]([CH3:13])[N:15]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CNN
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1O

Procedure:
To ethyl 4,4,4-trifluoroacetoacetate (18 mL, Aldrich) in ethanol (200 mL) was added methyl hydrazine (6.6 mL) in ethanol (50 mL). The mixture was refluxed for 16 h and concentrated in vacuo leaving a white solid. Recrystallization from EtOAc/toluene (50:50) gave pure 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[CH:7][CH:8]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([NH2:12])[C:2]([NH2:1])=[CH:3]2)=[CH:8][CH:7]=1
Reactant: Nc1cc2cc(Cl)ccc2cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc2ccc(Cl)cc2cc1N

Procedure:
To 0.025 mole of the 2-amino-7-chloro-3-nitronaphthalene (prepared in Example 2) in 100 ml of 95% ethanol is added a solution of 3.4 equivalents of sodium hydrosulfite (Na2S2O4) in a solution of 100 ml of water and 15 ml concentrated (28%) ammonium hydroxide. The mixture is refluxed for 5 minutes and an amount of hydrosulfite solution equal to 10% of the original is added to the relfuxing mixture. TLC (silica gel, ether) indicates consumption of starting material. The mixture is concentrated to one-half its original volume under vacuum and the residual mixture extracted with two 150 ml portions of chloroform. The combined chloroform extracts are dried (Na2SO4), filtered, and evaporated to dryness to yield the crude title compound which is used without further purification in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=[O:14])=[CH:4][CH:3]=1.Cl.[CH3:30][O:31][NH2:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28]3)=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18]/[C:17]/2=[N:32]\[O:31][CH3:30])=[O:14])=[CH:6][CH:7]=1
Reactant: CON
Reactant: O=C(N[C@H]1CCCCC1=O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Solvent: CO
Product: CO/N=C1\CCCC[C@@H]1NC(=O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution under of 100 mg of 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-((S)-2-oxo-cyclohexyl)-nicotinamide in 1 ml methanol was added 105 mg O-methylhydroxylamine hydrochloride and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 0.039 g of the title compound as white foam. MS (EI): 402.3 (M+H).