Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([O:14][CH3:15])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol), N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57%). MS (ES+) C9H10FNO2 requires: 183. found 184 [M+H]+; purity: 90% (UV254).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:25][CH3:26])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCCCCCCCCCCCCO

Procedure:
To a solution of 5.0 g of 16-hydroxyhexadecanoic acid in 100 ml of ethanol was added 0.2 ml of sulfuric acid and the mixture was heated under reflux for one hour. The reaction solution was distilled off under reduced pressure. The residue was diluted with ethyl acetate and washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then distilled under reduced pressure to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:31](=[O:32])[CH2:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)Cc1ccccc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)Cc4ccccc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (100 mg, 0.32 mmol) and phenylacetyl chloride (51 μl, 0.38 mmol). The title compound was obtained as yellow powder (48 mg, 34%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[N:19][CH:20]=1)[CH3:14].[O:22]1CCC[CH2:23]1>>[CH2:13]([C:15]1[CH:16]=[C:17]([CH:23]=[O:22])[C:18]([F:21])=[N:19][CH:20]=1)[CH3:14]
Reactant: C1CCOC1
Reactant: CCc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CCc1cnc(F)c(C=O)c1
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.01 mL, 7.19 mmol) in tetrahydrofuran (20 mL) was treated in ice-bath with n-butyllithium (2.5M, 2.9 mL, 7.19 mmol) and stirred for 30 min. The resulting solution was reacted at −78° C. with 5-ethyl-2-fluoropyridine (2-b, 0.75 g, 5.99 mmol), stirred for 4 h, and treated with N,N-dimethylfornmamide (482 mg, 6.59 mmol). The reaction mixture was quenched with acetic acid (1 mL), partitioned between ethyl acetate and water. The organic layer washed with 0.5N—HCl and then with brine, separated, dried (MgSO4) and concentrated in vacuo. Chromatography (30% ethyl acetate in hexanes) afforded the desired compound (2-f); 1H NMR (500 MHz, CDCl3) δ10.3 (s, 1 H), 8.29 (d, 1 H, J=2.0 Hz), 8.12 (dd, 1 H, J=9.0, 2.5 Hz), 2.73 (q, 2 H, J=7.8 Hz), 1.29 (t, 3 H, J=7.5 Hz).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]([C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1)=O.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[O:9]=[C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:11]([C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=2)[NH:10]1
Reactant: NC(=O)COc1ccc(C=O)cc1
Reactant: NC(=O)c1ccccc1N
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: NC(=O)COc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Yield: 56 %

Procedure:
2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide was synthesized from anthranilamide and 2-(4-formyl-phenoxy)-acetamide, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide (183 mg, 56%) was isolated as a light beige solid. Selected data: MS (m/z): 295.97; MP 277.5-278.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[CH3:4][C:1]([CH3:2])([O:5][C:6]([NH:8][CH:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:24][CH2:23][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:25])=[O:16])=[O:7])[CH3:3]
Reactant: CCOC(=O)CCN
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)C(CCSC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-methionine (6.2 g) in DMF (25 ml) and pyridine (25 ml) was treated with DSC (9.6 g) and a catalytic amount of DMAP. After 4 hours, a solution of β-alanine ethyl ester HCl (3.8 g) and K2CO3 (3.5 g) in saturated aqueous NaHCO3 (25 ml) was added. The reaction mixture was stirred overnight at room temperature. The excess solvent was removed under reduced pressure and purified by HPLC (RP--CH3CN/H2O). N-[2-[[(1,1-dimethylethoxy)carbonyl]-amino]-4-(methylthio)-1-oxobutyl]-β-alanine, ethyl ester (7.0 g) as a colorless oil was obtained. The oil was confirmed as the desired product by MS and used without further purification.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](N(CC)CC)C.C(OC(=O)C)(=O)C.C(OCC)(=O)C>ClCCl.O>[CH3:28][NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]2[CH:26]=[CH:27][C:14]([C:12]3[N:13]=[C:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[NH:10][CH:11]=3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reaction time: 20 h

Procedure:
4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (238 mg, 0.0066 mol), (prepared according to a method analogous to that described in Example 28) is suspended in dichloromethane (5 ml) at 23° C. Triethylamine (0.1 ml, 0.0079 mol) and acetic anhydride (0.062 ml, 0.0066 mol) are added. The mixture is then stirred for 20 hours then evaporated to dryness. The oil obtained is taken up with ethyl acetate and water. After decantation and extraction by ethyl acetate, the organic phase is washed with water then with a saturated solution of sodium chloride, dried over sodium sulphate then the solvent is evaporated off. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 7-3 to 9-1). After washing with diisopropyl ether and isopentane, a beige-coloured powder is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C)C=O.[Cu]>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: Brc1ccccn1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 4-hydroxybenzoate (25.3 g, 111 mmol) in N,N-dimethylformamide (60 ml) was added potassium tert-butoxide (12.4 g, 111 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure and 2-bromopyridine (24.5 g, 155 mmol), a copper powder (1.76 g, 27.7 mmol) and N,N-imethylformamide (80 ml) were added. The mixture was stirred at 120° C. for 8 hrs. The reaction solution was filtered with celite, and the filtrate was evaporated under reduced pressure. To the residue was added water (500 ml), and the mixture was extracted with ethyl acetate (500 ml). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). Recrystallization from ethyl acetate-hexane gave the objective substance (25.5 g, 73%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20]C)=[O:19])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CO>[CH2:3]([O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])[CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC/C=C\CCCOc1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC/C=C\CCCOc1cccc(C(=O)O)c1
Yield: 95.8 %

Procedure:
4 mL of 1 N sodium hydroxide solution (4.0 mmol) are added portionwise to 1.14 g of 15 (3.74 mmol) in methanol (30 mL). The solution is refluxed overnight. A further 4 mL of 1 N sodium hydroxide solution are added, and the mixture is refluxed for a further 1 hour 30 minutes. After evaporating off the solvent, the reaction medium is acidified with 0.5 N HCl and extracted with DCM. 1.04 g of a yellow oil are obtained, i.e. a yield of 96%.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7](/[CH:15]=[CH:16]/[C:17](O)=[O:18])[C:6]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:65][CH2:66][CH2:67][CH:68]1[CH2:72][CH2:71][CH2:70][N:69]1[CH3:73].[Li+].[OH-]>CN(C=O)C>[CH3:73][N:69]1[CH2:70][CH2:71][CH2:72][CH:68]1[CH2:67][CH2:66][NH:65][C:17](=[O:18])/[CH:16]=[CH:15]/[C:7]1[C:6]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[C:5]([C:3]([OH:2])=[O:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: COC(=O)c1c2c(cc(/C=C/C(=O)O)c1NS(=O)(=O)c1ccccc1)CCCC2
Reactant: CN1CCCC1CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC1CCNC(=O)/C=C/c1cc2c(c(C(=O)O)c1NS(=O)(=O)c1ccccc1)CCCC2
Temperature: 55 °C

Procedure:
A mixture of Example 476D (20 mg, 0.05 mmol) in DMF (1.0 mL) was treated with macroporous polystyrene bound DCC resin (105 mg, 0.14 mmol), 1-hydroxybenzotriazole hydrate (7 mg, 0.05 mmol), diisopropylethylamine (0.026 mL, 0.15 mmol) and 2-(aminoethyl)-1-methylpyrrolidine (0.010 mL, 0.07 mmol), heated to 55° C. for 16 hours, and concentrated. The concentrate was dissolved in 0.5 mL 2:1 dioxane/water, treated with LiOH (13 mg, 0.3 mmol), and heated to 160° C. for 27.5 minutes in a microwave reactor. The reaction mixture was concentrated and the residue was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 512 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.89 (br s, 1H), 9.37 (br s, 1H), 7.99 (t, 1H), 7.61 (d, 2H), 7.54 (t, 1H), 7.46-7.43 (m, 3H), 7.31 (s, 1H), 6.28 (d, 1H), 3.23 (m, 4H), 3.08 (m, 1H), 2.84 (d, 3H), 2.75 (m, 2H), 2.65 (m, 2H), 2.30 (m, 1H), 2.04 (m, 2H), 1.90 (m, 1H), 1.71-1.63 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH2:57][C:58]#[CH:59])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:61])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[Na+].[I-:63]>CC(C)=O>[CH2:57]([O:56]/[N:55]=[C:29](/[C:30]1[N:31]=[C:32]([NH:35][C:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:33][CH:34]=1)\[C:28]([NH:27][CH:26]1[C:25](=[O:61])[N:7]2[C:8]([C:9]([O:11][CH:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])=[C:3]([CH2:2][I:63])[CH2:4][S:5][C@H:6]12)=[O:60])[C:58]#[CH:59]
Reactant: [I-]
Reactant: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of diphenylmethyl 3-chloromethyl-7-[(Z)-2-propargyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VI-7) (2.0 g, 2.3 mmoles) and NaI (1.04 g, 6.9 mmoles) in acetone (40 mL) was stirred for 1 hour. The mixture was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous Na2S2O3, water and a saturated aqueous NaCl, successively. It was then dried over MgSO4 and evaporated to give 2.2 g (98%) of the title compound [VII-7].
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].C(N(CC)CC)C.[C:14]([O:18][C:19]([O:21]N=C(C1C=CC=CC=1)C#N)=O)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O>[CH3:17][C:14]([CH3:15])([O:18][C:19]([N:1]([CH3:2])[CH2:3][C:4]([OH:6])=[O:5])=[O:21])[CH3:16]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNCC(=O)O
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CC(=O)O)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
A mixture of sarcosine (1.5 g., 16.7 mmole), triethylamine (3.5 ml., 1 eq.), and water (10 ml.) is treated with 2-(t-butyoxycarbonyloxyimino)-2-phenylacetonitrile (4.5 g., 1.1 eq.) in dioxane (10 ml.) at 25°. After 3 hours, the reaction mixture is diluted with water and then washed twice with ethyl acetate. The aqueous phase is acidified to pH 3.0 with 10% citric acid and the resulting oil is extracted with ethyl acetate (twice). The combined extracts are washed with brine, dried (MgSO4), and evaporated to give 3.0 g. of N-[(1,1-dimethylethoxy)carbonyl]-N-methylglycine as a viscous oil which crystallizes on standing; m.p. 84°-85.5°. Tlc (dichloromethane/methanol/acetic acid; 100:5:5) shows a single spot at Rf 0.6.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([CH3:22])[CH:10]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([CH3:22])[CH:10]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C)c1NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(CN)cc(C)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 464.2 %

Procedure:
(4-Methanesulfonylamino-3-methyl-5-vinylbenzyl)carbamic acid tert-butyl ester (85.9 mg, 0.09 mmol) was dissolved in CH2Cl2. 5˜6 drops of CF3COOH were added. The reaction mixture was stirred for 12 hr. The reaction mixture was concentrated to yield brownish syrup (100.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.C([O-])=O.[NH4+]>[Pt].CO>[NH2:21][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Pt]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(Br)cc1NC1CCN(C2CCOCC2)CC1
Reaction time: 1 h

Procedure:
688 mg (0.0018 mol, 1 eq) of N-(5-bromo-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine D10, 350 mg (0.00018 mol, 0.1 eq) of 10% platinum on carbon, 375 mg (0.0057 mol, 3.2 eq) of ammonium formate, and 20 mL of methanol (degassed with nitrogen) were combined and stirred for 1 hour. The catalyst was then filtered off, and the filtrate was evaporated. Water and dichloromethane were added and shaken. Separation and drying of the dichloromethane layer with sodium sulfate followed by evaporation yielded a crude product which was purified exactly as in Example 1 where A=H2O and B=CH3CN to yield (2-amino-5-bromophenyl)[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]amine, the title compound. MS (ESI): 355 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:12](OCC)=[O:13])C>C1COCC1>[CH2:31]([C:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:10][OH:9])[CH2:12][OH:13])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC(CO)(CO)CCCCCCCCCCCCCC
Reaction time: 0.5 h
Yield: 91 %

Procedure:
LAH (9.68 mmol) is added to a diethyl-2,2-ditetradecylmalonate (2.42 mmol) solution in THF at rt and the reaction mixture is heated under reflux for 2 h. The reaction mixture is quenched with 1 M HCl solution and stirred for 30 min. The aqueous layer is extracted with diethyl ether two times. The combined organic layers are washed with a dilute HCl solution and brine, and then dried over anhydrous magnesium sulfate. Solvents are evaporated under vacuum. The reaction afforded 2,2-ditetradecyl-1,3-propanediol in 91% yield 1H NMR (300 MHz, CDCl3): δ 3.57 (s, 4H, CH2O), 1.38-1.15 (m), 0.88 (t, 6H, J=8.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:6]=1.Cl[C:31]([F:36])([F:35])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:31]([F:36])[F:35])=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[CH2:22][S:23][CH2:24][C:25]([F:28])([F:26])[F:27])[CH:6]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)Cc1ccc(O)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
{4-Hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.40 g, 0.92 mmol), sodium chlorodifluoroacetate (0.282 g, 1.86 mmol), and potassium carbonate (0.14 g, 1.02 mmol) were combined in DMF:H2O (8.5:1; 4.6 mL) and degassed with N2 for 15 minutes. The reaction was then stirred at 100° C. for 4 hours. After work-up with EtOAc and 1N aqueous HCl, the residue was purified by silica gel chromatography to give {4-difluoromethoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.CN(C)C=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccc(C)cc3)c2c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
240 mg of 6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 0.2 ml of N,N-dimethylformamide and 0.7 ml of morpholine, and the mixture was stirred for 7.5 hours at 110° C. Another 0.7 ml of morpholine was added and heated for another 4 hours at 110° C. It was mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 7 mg was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24]([CH3:27])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[CH3:27][C:24]1[N:22]2[N:23]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)[C:19]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:20][C:21]2=[N:26][CH:25]=1
Reactant: Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12
Temperature: 25 °C
Yield: 16.2 %

Procedure:
18 mg (0.04 mmol) {1-[4-(3-Methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester (intermediate example Int-3-0) were dissolved in 01 mL dioxane. 0.4 mL 4M hydrogen chloride in dioxane were added and the mixture was stirred over night at room temperature. The solvent was evaporated and the residue was treated with saturated sodium bicarbonate solution. After stirring for one hour the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with water and dried (sodium sulfate). After removal of the solvent the residue was purified by chromatography on silicagel (eluents dichloromethane/methanol) and additional HPLC yielding 2.3 mg (14%) of the title compound.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.Cl[C:28]1[N:33]=[C:32]([NH:34][CH2:35][C:36]2[C:40]3[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:39]=3[S:38][CH:37]=2)[C:31]([F:46])=[CH:30][N:29]=1.C1COC2C=CC(N)=CC=2O1>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]2[S:38][CH:37]=[C:36]([CH2:35][NH:34][C:32]3[C:31]([F:46])=[CH:30][N:29]=[C:28]([NH:11][C:5]4[CH:6]=[CH:7][C:8]5[O:9][CH2:10][CH2:1][O:2][C:3]=5[CH:4]=4)[N:33]=3)[C:40]=2[CH:41]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Fc1cnc(Cl)nc1NCc1csc2ccc(Cl)cc12
Agent: Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1NCc1csc2ccc(Cl)cc12

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.08 (d, 1H, J=1.8 Hz), 8.02 (d, 1H, J=8.7 Hz), 7.97 (d, 1H, J=4.8 Hz), 7.63 (s, 1H), 7.42 (dd, 1H, J=1.8 and 9.3 Hz), 7.07 (bs, 1H), 6.85 (dd, 1H, J=2.4 and 8.7 Hz), 6.56 (d, 1H, J=8.7 Hz), 4.77 (s, 1H), 4.75 (s, 1H), 4.14 (s, 4H); LCMS: ret. time: 25.89 min.; purity: 97%; MS (m/e): 444 (MH+).