Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].CCCCCCC>CN(C)C=O>[Si:34]([O:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:13]3)[C:9]2=[O:28])[CH2:6][CH2:7]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCCC2(CCN([C@H]3CC[C@@H](O)CC3)C2=O)C1
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a stirred solution of benzyl 2-(cis-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (60.00 g, 155.2 mmol) in anhydrous N,N-dimethylformamide (160 mL) at r.t. was added 1H-imidazole (32.0 g, 466 mmol) and tert-butyldimethylsilyl chloride (36.2 g, 233 mmol). The reaction mixture was stirred at r.t. for 4 h, quenched with water (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (84 g). The pure product (55.4 g) was obtained by re-crystallization of the crude product from heptane. The mother liquor was concentrated and subjected to purification by flash chromatography on a silical gel column eluting with AcOEt/Haxane to give additional 14.4 g of the product with a total 89.7% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:54]=[CH:53][C:8]([C:9]([O:24][CH2:25][C@H:26]2[O:30][C@@H:29]([N:31]3[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]3=[O:33])[CH2:28][C@:27]2([CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)[OH:40])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][C:13](OC)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.C1C[O:58][CH2:57]C1>>[CH3:57][O:58][C:13]1[CH:12]=[CH:11][C:10]([C:9]([O:24][CH2:25][C@H:26]2[O:30][C@@H:29]([N:31]3[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]3=[O:33])[CH2:28][C@:27]32[CH2:41][O:40]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:53]=[CH:54][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]23CO3)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of NaH (60% in mineral oil, 0.18 g; 7.5 mmol) in anhydrous THF (18 ml) at 0° C. under argon was added dropwise a solution of 5′-O-(4,4′-dimethoxytrityl)-3′-p-toluensulfonyloxymethylthymidine (1.5 g; 2.06 mmol) in THF (10 ml). The resulting reaction mixture was stirred at room temperature for 2 h, cooled to 0° C., and quenched by addition of water. The mixture was diluted with EtOAc (250 ml), washed with water (2×200 ml), then with 10% NaHCO3 (2×200 ml), dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica (5% CH3OH in CH2Cl2) to yield 0.97 g (85%) of 5′-O-(4,4′-dimethoxytrityl)-3′-C,O-methylene thymidine as a foam.
Reaction SMILES: [N:1]1(C2C=CC(NC3C4N(C=CN=4)C(C4C=CNC(=O)C=4)=CN=3)=CC=2)CCOCC1.C(OC(=O)[N:36]([C:53]1[C:54]2[N:55]([CH:60]=[CH:61][N:62]=2)[C:56](Br)=[CH:57][N:58]=1)[C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[C:39]([CH2:49][N:50]([CH3:52])[CH3:51])[CH:38]=1)(C)(C)C.CC1(C)C(C)(C)OB([C:72]2[CH:73]=[N:74][NH:75][CH:76]=2)O1.CC([O-])(C)C.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.O>[NH3:1].[CH3:52][N:50]([CH2:49][C:39]1[CH:38]=[C:37]([NH:36][C:53]2[C:54]3[N:55]([CH:60]=[CH:61][N:62]=3)[C:56]([C:72]3[CH:73]=[N:74][NH:75][CH:76]=3)=[CH:57][N:58]=2)[CH:42]=[CH:41][C:40]=1[N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[CH3:51]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)Cc1cc(N(C(=O)OC(C)(C)C)c2ncc(Br)n3ccnc23)ccc1N1CCOCC1
Reactant: O=c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)ccc1N1CCOCC1
Product: N
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
In the same way as described for Compound 85, step 1, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(3-dimethylaminomethyl-4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (54 mg, 0.1024 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (29.8 mg, 0.153 mmol), Pd(PPh3)4 (12 mg, 0.0102 mmol) and NaOtBu (39 mg, 0.41 mmol) in 3:1 DMF/water (4 mL). The reaction mixture is concentrated under reduced pressure and the residue is dissolved in a mixture 1:1 DCM:TFA (drop of water). After stirring the solution at room temperature for 4 hours, ethyl acetate is added and the mixture is basified using sat. NaHCO3. The organic layer is separated, dried over MgSO4, filtered and concentrated in vacuo to afford a crude compound. Purification by silica gel column chromatography eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), affords the title compound (28.1 mg, 66%). Conversion into the mesylate salt using 0.1M MsOH (0.67 mL) yields the title compound (26.9 mg, 78%). LCMS: Rt 1.97 min (97%), m/z (APCI) 419 (M+H)+, 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.35 (3H, s, MsOH), 2.74-2.89 (10H, m), 3.82 (4H, m), 4.39 (2H, d), 7.42 (1H, d), 7.61 (1H, s), 7.81 (1H, s), 8.08 (1H, d), 8.14-8.26 (4H, m), 9.19 (1H, br s), 9.75 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[C:19]1([CH2:25][CH2:26][NH:27][CH2:28]/[CH:29]=[CH:30]/[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][C:5]=1[CH2:6][N:27]([CH2:26][CH2:25][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:28]/[CH:29]=[CH:30]/[C:31]([O:33][CH3:34])=[O:32])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: COC(=O)/C=C/CNCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C/CN(CCc1ccccc1)Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 2-nitro-4-(t-butoxycarbonyl)-benzylbromide (4.06 g, 12.8 mmol) in THF (50 mL), methyl 4-(phenylethylamino)-crotonate (3.4 g, 15.5 mmol) was added with stirring at RT. Triethylamine (2.2 mL, 15.7 mmol) was then added. After stirring for 16 h, the reaction was diluted with ethyl acetate and washed with 1N sodium carbonate, brine, dried (sodium sulfate) and concentrated. Flash chromatography (silica gel, 15% ethyl acetate/n-hexane) gave the title compound as an oil (5.16 g, 88%). 1H-NMR (CDCl3) δ1.60(9H, s), 2.74(4H, br s), 3.30(2H, dd), 3.74(3H, s), 4.00(2H, s), 6.00(1H, d, J=15 Hz), 7.02(1H, dt), 7.25(5H, m), 7.67(1H, d, J=8 Hz), 8.15(1H, dd), 8.45(1H, d, J=2 Hz).
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:9]>O1CCCC1>[OH:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:8])[CH2:1]1
Reactant: O=C1CCCCC2OC12
Solvent: C1CCOC1
Product: O=C1CCCCC(O)C1
Reaction time: 2 h
Yield: 97 %

Procedure:
To a 25° C. solution of 45.9 g. (0.364 mole) of 8-oxabicyclo[5.l.0]octan-2-one in 950 ml. of 10% aqueous tetrahydrofuran was added 39.7 g. (1.47 mmoles) of aluminum amalgam. (The aluminum amalgam was prepared by 15-30 second successive washing of small pieces of aluminum foil with 2N sodium hydroxide, distilled water, 0.5% mercuric chloride, distilled water, 2N sodium hydroxide, distilled water, 0.5% mercuric chloride, distilled water, ethanol and ether.) The mixture was stirred for 2 hours, then filtered through diatomaceous earth. The filtrate was evaporated on a rotovapor, the residue saturated with solid sodium chloride and extracted with three 500 ml. portions of ether. The ether extract was dried over magnesium sulfate and evaporated to yield 45 g. (97%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[S:27]([NH2:30])(=[O:29])=[O:28].I[CH2:32]S(N)(=O)=O.Cl>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1([CH3:32])[C:7]2[C:8]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:5])[CH3:2]
Reactant: NS(=O)(=O)CBr
Reactant: CCOC(=O)C1c2ccccc2-c2ccccc21
Reactant: NS(=O)(=O)CI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C)c2ccccc2-c2cccc(S(N)(=O)=O)c21
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of fluorene-9-carboxylic acid ethyl ester (1) (11 g, 46.2 mmoL), potassium carbonate (6.4 g, 46.2 mmoL, 1 eq) and a mixture of bromomethanesulfonamide and iodomethanesulfonamide [prepared from bromomethanesulfonyl chloride see, Trice et al., J. Org. Chem., 32, 990(1967) by reaction with ammonia gas in cold ether followed by reaction with excess sodium iodide in refluxing acetonitrile] (9.1 g, 1 eq) in dry dimethylformamide (100 mL, from sieves) was stirred under nitrogen for 18 h. Water (200 mL) was then added and the solution was acidified with 1N aqueous hydrochloric acid (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were then washed with brine (3×200 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel using 40% ethyl acetate in hexane to provide 4.8g (31%) of product (2): mp 150°-156° C.; IR (KBr) 3360, 1710, 740, 725 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.78-7.69 (m, 4 H), 7.50-7.32 (m, 4 H), 4.38 (bs, 2 H, exchangeable), 4.12 (q. 2 H), 4.11 (s, 2 H), 1.12 (t, 3 H), MS m/z 331 (M+), 178 (base peak).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 91 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.28 (s, 4H), 3.86 (s, 3H), 4.08-4.19 (m, 4H), 7.01-7.08 (m, 3H), 7.17-7.37 (m, 1H), 7.49-7.61 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH2:51][C:52]([NH:54][C@H:55]([B:68]2[O:76][CH:75]3[C:70]([CH3:80])([CH:71]4[CH2:77][CH:73]([CH2:74]3)[C:72]4([CH3:79])[CH3:78])[O:69]2)[CH2:56][C:57]2[C:58]([O:66][CH3:67])=[C:59]([CH:63]=[CH:64][CH:65]=2)[C:60]([OH:62])=[O:61])=[O:53])[CH2:47][CH2:46]1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH2:51][C:52]([NH:54][C@H:55]([B:68]2[O:76][CH:75]3[C:70]([CH3:80])([CH:71]4[CH2:77][CH:73]([CH2:74]3)[C:72]4([CH3:79])[CH3:78])[O:69]2)[CH2:56][C:57]2[C:58]([O:66][CH3:67])=[C:59]([CH:63]=[CH:64][CH:65]=2)[C:60]([OH:62])=[O:61])=[O:53])[CH2:47][CH2:46]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](N)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](NC(=O)CNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(tert-butoxycarbonylamino)acetic acid (175 mg) in a flask was added HATU (380 mg) and N-methyl morpholine (0.56 mL). After stirring at RT for 1 hr, this solution was added to 3-((2R)-2-(2-(trans-4-aminocyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoic acid from Step 1 of Example 53 (110 mg) in DMF (3 mL). The resultant reaction mixture was stirred at RT overnight. Water was added to the reaction mixture and extracted with EtOAc. The organic phase was dried and concentrated in vacuo to afford the crude product which was used in next step without further purification.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>CS(C)=O>[Cl:3][C:4]1[N:5]=[N:6][C:7]([O:18][C:14]2[CH:13]=[C:12]([NH2:11])[CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccc(Cl)nn2)c1

Procedure:
A concentrated aqueous solution of 44 g of sodium hydroxide was added to a stirred solution of 149 g of 3,6-dichloropyridazine and 114.5 g of meta-aminophenol in 500 ml of dimethyl sulfoxide, at room temperature. The stirred mixture was heated, refluxed (150°-155° C.) for two hours, cooled, and filtered. The filter cake was recrystallized from aqueous methanol to give 3-(6-chloro-3-pyridazinyloxy)benzeneamine (1A), as an off-white solid, mp: 76°-77° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH3:11])=[N:8][CH:9]=1.Br[CH2:13][C:14]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].O>O1CCCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:14]([CH2:13][N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=2)[CH3:11])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: CNc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)ccc1CN(C)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 46 mg, 1.1 mmol) in tetrahydrofuran (4 ml) was added 5-chloro-N-methylpyridin-2-amine (128 mg, 1.14 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred for 30 min. The mixture was added methyl 2-(bromomethyl)-5-chlorobenzoate (250 mg, 0.95 mmol) in tetrahydrofuran (5 ml) at room temperature and stirred at 80° C. for 8 hr. After cooling to room temperature, the mixture was added water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 102 mg (33%) of the title compound:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([NH2:16])=[C:11]([CH3:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>Cl>[NH2:16][C:12]1[C:11]([CH3:17])=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:19]([CH3:18])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:7]=2)=[C:14]([CH3:15])[CH:13]=1
Reactant: Cc1cc(Oc2ccnc(Cl)n2)c(C)cc1N
Reactant: CNc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccnc(N(C)c3ccccc3)n2)c(C)cc1N

Procedure:
A solution of 2.50 g (10 mmol) 4-(2-chloro-pyrimidin-4-yloxy)-2,5-dimethyl-phenylamine and 2.14 g N-methylaniline (20 mmol) in 50 ml hydrochloric acid were stirred for 20 h at 80° C. After cooling down to ambient temperature 50 ml ethyl acetate was added and the organic layer was separated. The water layer was brought to pH 8 with sodium carbonate and the formed precipitate was filtered by suction and washed with hexane. After separation the organic layer was concentrated in vacuo and column chromatography (dichloromethane) yielded 380 mg (11%) with a purity of 89% log P (pH=2.3)=1.72.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].[OH-].[K+]>CCOCC>[S:1]([O:16][CH:13]([C:14]#[CH:15])[CH3:12])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of tosyl chloride (0.5 mole) and commercial 3-butyn-2-ol (0.4 mole; 40-50% aqueous solution) in ether (350 ml), potassium hydroxide (2.5 moles) is slowly added over a period of 15-30 minutes. The temperature is maintained at 0°-5° C. for the entire period and the reaction mixture is allowed to stand for 90 minutes. When the reaction is complete, the ether phase is washed and dried. Removal of the ether, in vacuo, yields crude 2-tosyloxy-3-butyne.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH:15]O>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][C:6]([OH:15])=[CH:5]2
Reactant: OO
Reactant: O=[N+]([O-])c1cc(F)cc2cccnc12
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)cc2cc(O)cnc12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A solution of 6-fluoro-8-nitro-quinoline (900 mg, 4.7 mmol) in acetic acid (10 ml) was treated at room temperature with hydrogen peroxide (30% in water (1.6 ml), then it was stirred at 70° C. for 5 hours. For the workup, the reaction mixture was cooled and poured into ice-water. The precipitate was filtered, washed with water, collected and dried. 6-Fluoro-8-nitro-quinolin-3-ol was obtained as a brown solid (285 mg, 29%); (calculated) C9H5FN2O3 [208.2]; (found) [M−H]−=207.
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:8]1[CH2:9][C@@H:6]([N:18]=[N+:19]=[N-:20])[CH2:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 85 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (29 g, 109 mmol) in DMF (100 mL) was added sodium azide (5.68 mL, 162 mmol, Sigma-Aldrich Chemical Company, Inc.) portionwise and the mixture stirred at 85° C. for 18 h. The reaction was diluted with water (200 mL) after cooling and extracted with EtOAc (3×100 mL). The combined organic was washed with water (2×100 mL) and brine, dried over Na2SO4 and evaporated in vacuo to give product tert-butyl(cis-3-azidocyclobutyl)carbamate (22 g, 104 mmol, 95% yield) that was used in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35].[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C:44](=[O:51])[CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1>C1COCC1>[Cl:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1[CH:34]([CH3:35])[C:44]([C:38]1[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=1[F:36])([OH:51])[CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1
Reactant: CCc1ccncc1Cl
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(c1ccncc1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -20 °C

Procedure:
To a solution of diisopropylamine (1.01 g, 10 mmol) in dry THF (60 ml) at -60° C. and under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane (6.25 ml, 10 mmol). The mixture was allowed to warm to -20° C. then recooled to -70° C. and to the resulting solution of lithium diisopropylamide (LDA) (10 mmol) at -70° C. was added dropwise 3-chloro-4-ethylpyridine (see D. L. Comins et al, Heterocycles, 22, 339 (1984)) (1.41 g, 10 mmol). The resulting mixture was stirred at this temperature for 15 minutes after which time a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.23 g, 10 mmol) in THF (15 ml) was added. This mixture was allowed to warm to room temperature over a 30 minute period and the reaction was quenched by the addition of water (30 ml) and extracted with ethyl acetate (3×60 ml). The combined organic extracts were dried over magnesium sulphate, filtered, concentrated under reduced pressure and the title compound isolated by "flash" chromatography on silica eluting with ethyl acetate. The product was recrystallized from ethyl acetate (yield=0.46 g), m.p. 182°-184° C. Found: C,55.76; H,4.15; N,15.23; C17H15ClF2N4O requires: C,55.98; H,4.14; N,15.36%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:5]=[CH:6][CH:7]=1.Cl[C:22]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([S:34][CH3:35])[N:23]=1>>[O:20]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18](=[O:19])[N:10]1[CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([S:34][CH3:35])[N:23]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(CCN2C(=O)c3ccccc3C2=O)c1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1cccc(CCN2C(=O)c3ccccc3C2=O)c1

Procedure:
The compound was prepared from 2-[2-(3-aminophenyl)ethyl]-1H-isoindole-1,3(2H)-dione and ethyl 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarboxylate following a synthetic route similar to that described for intermediate 11.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:40][C:41]1[CH:42]=[C:43]([CH:55]=[CH:56][CH:57]=1)[CH2:44][C:45]1([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[C:7]([NH:40][C:41]2[CH:42]=[C:43]([CH:55]=[CH:56][CH:57]=2)[CH2:44][C:45]2([C:48]([O:50][C:51]([CH3:54])([CH3:52])[CH3:53])=[O:49])[CH2:47][CH2:46]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C(F)(F)F)cc3)C3CCCC3)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3.0 g (11.02 mmol) of (+/−)-cyclopentyl[4-(trifluoromethyl)phenyl]acetic acid were dissolved in 16.0 ml of DMF, and 1.79 g (13.22 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added. The mixture was cooled to 0° C., and 3.8 ml (22.04 mmol) of N,N-diisopropylethylamine and 3.41 g (13.77 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, dissolved in a little DMF, were added. 5.03 g (13.22 mmol) of HATU were then added in several portions, and the reaction mixture was slowly warmed to RT and then stirred at RT for 3 h. The reaction was then added to water. After phase separation, the aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1). This gave 4.89 g of the target compound (88.5% of theory).