Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:15]2[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([C:1]34[CH2:8][CH:7]5[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]5)[CH2:10]3)[CH2:2]4)[CH:16]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COc1ccc(I)cc1C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(Br)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 42.8 %

Procedure:
To a stirred solution of 2-(1-admantanyl)-4-iodo-1-methoxybenzene (0.19 g; 0.5 mmol) and 4-bromophenylboronic acid (0.1 g, 0.47 mmol) in 1,4-dioxane (10 ml) Pd(PPh3)4 (0.04 g) was added at 80° C., followed by the addition of the solution of NaHCO3 (0.2 g) in H2O (2 ml). The mixture was stirred at reflux for 2 h and the solvents were evaporated. The residue was diluted to 100 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4, filtered and the filtrate was evaporated to dryness to give The residue was purified by FCC (SiO2) to give the title product (0.08 g; 39%), as creamy gum. 1H-NMR (CDCl3) 1.77 (s, 6H); 2.07 (s, 3H); 2.12 (s, 6H); 3.86 (s, 3H); 6.92 (d, 1H, J=8.39 Hz); 7.34 (dd, 1H, J=2.42, 8.42 Hz), 7.38-7.42 (m, 3H); 7.50 (d, 2H, J=8.57 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C@@H:8]([C:16](N1[C@H](C)[C@H](C2C=CC=CC=2)OC1=O)=[O:17])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[OH:32]O>C1COCC1.O>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])[C:16]([OH:17])=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ester 138 (2.65 g, 6.14 mmol) in 20 mL THF at 0° C. was added a precooled (0° C.) solution of LiOH monohydrate (1.0 g, 23.8 mmol) and hydrogen peroxide (30 wt % aqueous soln, 5.0 mL) in 10 mL H2O. The mixture was stirred vigorously for 90 minutes, then warmed to ambient temperature and stirred 90 minutes. The reaction was quenched at 0° C. by addition of 100 mL 10% NaHSO3 (aq), then extracted with Et2O. The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. The crude acid 139 was used without purification.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[CH2:17][CH:16]3[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:15]3)[CH2:11]2)=[CH:7][CH:6]=1)#[N:4].Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>O>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([CH2:29][N:21]([CH2:20][CH2:19][N:14]2[CH2:15][CH:16]3[O:18][CH:12]([CH2:11][N:10]([CH2:9][C:8]4[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:27][CH:26]=4)[CH2:17]3)[CH2:13]2)[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:31][CH:32]=1)#[N:35]
Reactant: CS(=O)(=O)NCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)N(CCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.9 %

Procedure:
To a suspension of sodium hydride (0.013 g of a 60% suspension in mineral oil, washed with pentane) in anhydrous N,N-dimethylformamide (4 mL) was added N-{2-[7-(4-Cyano-benzyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethyl}-methanesulfonamide (0.109 g, 0.30 mmol) at 0° C. The mixture was stirred for 2 hours while the temperature was allowed to warm to room temperature. At 0° C., 4-bromomethyl-benzonitrile (0.065 g, 0.33 mmol) was added. The mixture was stirred for 2 hours at room temperature, whereupon water (5 mL) was added. The aqueous layer was extracted with dichloromethane (3×5 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia dichloromethane as eluent, which afforded 79 mg (54.9%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:18])[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CS(C)=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:18])[N:4]([CH3:19])[C:3]1=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cn1c(N2CCN(CCCN)CC2)cc(=O)n(C)c1=O
Solvent: CS(C)=O
Product: Cn1c(N2CCN(CCCNc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O

Procedure:
2.50 g of the previously obtained compound h and 1.90 g of 4-nitrofluorobenzene were added to 20 ml of dimethyl sulfoxide, and the resultant mixture was then heated at 80° C. for 3 hours. After the mixture was allowed to stand for cooling, the precipitated crystals were collected by filtration, washed, and then dried to obtain 2.75 g of 1,3-dimethyl-6-[4-(3-[4-nitroanilino]-propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:9]([C:11]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:10])(=[O:8])=[O:7].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:69]([O:73][C:74]([NH:76][CH2:77][C:78]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:79]=1[C:80](O)=[O:81])=[O:75])([CH3:72])([CH3:71])[CH3:70]>ClCCl>[C:69]([O:73][C:74]([NH:76][CH2:77][C:78]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:79]=1[C:80]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:9]([C:11]1[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[C:18]([O:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:10])(=[O:8])=[O:7])=[O:81])=[O:75])([CH3:72])([CH3:70])[CH3:71]
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCN)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCNC(=O)c2cc(F)ccc2CNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a solution of methyl 5-(4-amino-N-methylbutylsulfonamido)-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 3.2; 5.52 mmol) in dichloro methane (5 mL) was added DIPEA (18.7 mmol) and HBTU (5.63 mmol). The mixture was stirred for 5 min at rt. 2((Tert-butoxycarbonylamino)methyl)-5-fluorobenzoic acid (4.69 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was washed with a 1M Na2CO3 solution. The aqueous phase was extracted with dichloro methane, dried and was concentrated. The crude product was purified by SiO2 column chromatography (5:1 to 1:1 hexanes:ethyl acetate) to give the target compound in 49% yield.
Reaction SMILES: [OH:1][CH:2]1[C:7]2([CH2:18][OH:19])[O:8][CH:9]([N:10]3[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]3=[O:17])[CH:3]1[O:4][N:5]([CH3:20])[CH2:6]2.[CH3:21][O:22][C:23]1[CH:44]=[CH:43][C:26]([C:27](Cl)(C2C=CC=CC=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:44][CH:43]=2)[O:19][CH:18]([C:23]2[CH:44]=[CH:43][CH:26]=[CH:25][CH:24]=2)[C:7]23[CH:2]([OH:1])[CH:3]([CH:9]([N:10]4[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]4=[O:17])[O:8]2)[O:4][N:5]([CH3:20])[CH2:6]3)=[CH:33][CH:32]=1
Reactant: CN1CC2(CO)OC(n3ccc(=O)[nH]c3=O)C(O1)C2O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C23CN(C)OC(C(n4ccc(=O)[nH]c4=O)O2)C3O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
To a solution of compound 55 (1 mmol) in anhydrous pyridine (4 mL) was added 4,4′-dimethoxytrityl chloride (1.5 mmol). After stirring at room temperature for 6 hours the mixture was quenched with MeOH and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL), washed with saturated aqueous NaHCO3 (2×20 mL), brine (20 mL) and the organic layer dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography. Appropriate fractions were collected, concentrated to give compound 56 in 80% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:15]2[CH:14]=[CH:13][C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:10]=2[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:8]=1)=[O:6].[H-].[Na+].O.Cl>CN(C)C=O>[N:4]1([C:5]([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][C:10]=3[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1nc(C(=O)NCCCl)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C(=O)N2CC2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 5 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A solution of 0.2 g of 6,6-diphenyl-1 (2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid (2-chloroethyl)amide in 7 cm3 of dimethylformamide is added dropwise to a suspension of 0.023 g of sodium hydride (at 60% in oil) in 3 cm3 of dimethylformamide cooled to a temperature in the region of 5° C. The reaction mixture is stirred for two hours at a temperature in the region of 20° C. The solution obtained is poured into a mixture of 30 cm3 of water and 0.3 cm3 of aqueous 1N hydrochloric acid solution while maintaining the temperature in the region of 5° C., and the mixture is extracted with three times 30 cm3 of ethyl acetate. The combined organic phases are washed with three times 30 cm3 of water and 30 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: cyclohexane/ethyl acetate (70/30 by volume)], 0.078 g of aziridin-1-yl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone is thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[I:12][CH2:13][S:14][C:15]1[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1>C(Cl)(Cl)Cl>[I:12][CH2:13][S:14]([C:15]1[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:9]
Reactant: Clc1cnc(SCI)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(CI)c1ncc(Cl)cn1
Reaction time: 8 h
Yield: 24 %

Procedure:
90% m-chloroperbenzoic acid 8.4 mmol) in chloroform (8 ml) was added dropwise for 10 min with stirring to a solution of 2-(iodomethyl)thio-5-chloropyrimidine in chloroform (7 ml) at -5° C. The reaction mixture was coloured violet during the addition. The mixture was left at room temperature overnight. The chloroform solution was then extracted with 1 M K2CO3, washed with a little water, then dried (MgSO4) solution evaporated and the product subjected to thick-layer chromatography. 2-(Iodomethyl)sulfinyl-5-chloropyrimidine: yield 24%, m.p. 158° C., IR (KBr): 1050 and 1090 cm-1 (SO).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Br:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH2:1][Br:17])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of 3,5-dimethylbromobenzene (70 g, 0.378 M), NBS (67.3 g, 0.373 M), and benzoyl peroxide (2.27 g, 0.009 M) in carbon tetrachloride (300 mL) was refluxed for 3 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a pale brown oil. The crude product was dissolved in hexane and filtered through a short silica gel pad (diameter: 9.5 cm, height: 7 cm). The silica gel pad was washed with hexane until the product eluted completely. The filtrate was evaporated in vacuo to give 94 g of 1-bromo-3-(bromomethyl)-5-methylbenzene (contaminated with starting material and 1-bromo-3,5-bis-bromomethylbenzene) as a pale brown oil, which solidified on standing at room temperature. The mixture was used directly in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[CH2:23][O:24][CH2:25][C:26](O)=[O:27])(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:52]3[CH2:53][NH:54][CH2:55][CH2:56][C:51]=3[O:50][N:49]=2)=[CH:44][CH:43]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:29])[C:6]([S:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[CH2:23][O:24][CH2:25][C:26]([N:54]2[CH2:55][CH2:56][C:51]3[O:50][N:49]=[C:48]([C:45]4[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=4)[C:52]=3[CH2:53]2)=[O:27])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: c1cc(-c2noc3c2CNCC3)ccn1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)O)c(C)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3CC[C@H]2COCC(=O)N2CCc3onc(-c4ccncc4)c3C2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-((1-(4-Methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-2-yl)methoxy)acetic acid (AC31) (0.13 g, 0.31 mmol) was dissolved in dichloromethane (4 ml) and 1,1′-carbonyldiimidazole (53 mg, 0.325 mmol) was added. After the mixture had been stirred at room temperature for 1 h, 3-(pyridin-4-yl)-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine (AM5) (62 mg, 0.31 mmol) in dichloromethane (4 ml) was added and the mixture was stirred at room temperature overnight. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, the aqueous phase was extracted with dichloromethane (2×) and the combined organic phases were washed with saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica) with ethyl acetate/hexane 20/1. Yield: 0.13 g (77%). MS, Rt=4.8 min, m/z=603.1 [MH]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:24]1COCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: C1CCOC1
Reactant: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Product: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanone (2.93 g, 6.73 mmol) in THF (80 mL) was added MeMgl solution (4.48 mL, 13.45 mmol). The resulting solution was allowed to stir at reflux for 5 hrs. Then the reaction mixture was cooled to room temperature, quenched with water, washed with NH4Cl solution and extracted by CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 2.2 g (yield: 95%) title compound which was used to next step without further purification. LCMS (method B): [MH]+=343, tR=2.05 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:11]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOc1cccc(N)c1
Product: CCOc1cccc(Nc2ncc(F)c(Nc3cccc(OCC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-ethoxyaniline were reacted to yield N2,N4-bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.96 (1H, d, J=4.8 Hz), 7.22 (m, 6H), 7.07 (t, 1H, J=1.8 Hz), 6.95 (dt, 1H, J=1.2 and 7.2 Hz), 6.77 (m, 2H), 3.88 (q, 4H, J=6.3 Hz), 1.33 (two t, 6H, J=6.3 Hz); 19F NMR (CDCl3): −46175; LCMS: ret. time: 26.86 min.; purity: 97%; MS (m/e): 369 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:13][C:9]([C:10]([NH:31][CH2:30][C:28]3[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=3)=[O:12])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)c(F)c2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC2CC2)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 6-(cyclopropylmethoxy)-5-(3,4-difluorophenyl)-nicotinic acid (example CD) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 455.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C1([O:23][C:24](=O)[NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([F:37])[CH:35]=3)[NH:30][CH:29]=2)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:24]([NH:25][CH2:26][CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([F:37])[CH:35]=3)[NH:30][CH:29]=2)=[O:23])[CH2:5][CH2:4]1
Reactant: O=C(NCCc1c[nH]c2ccc(F)cc12)Oc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)NCCc2c[nH]c3ccc(F)cc23)CC1

Procedure:
The more nonpolar diastereoisomer of 4-dimethylamino-4-phenyl-cyclohexylamine (218 mg, 1.0 mmole) was added to a solution of [2-(5-fluoro-1H-indol-3-yl)-ethyl]-carbamic acid phenyl ester (298 mg, 1.0 mmole) in dioxane (20 ml). The batch was then refluxed for 8 h. Working up was performed by removing dioxane by distillation and diluting the batch with water (10 ml). The batch was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and evaporated. The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexyl)-3-[2-(5-fluoro-1H-indol-3-yl)ethyl]urea was obtained after chromatography on silica gel with methanol as a colorless oil in a yield of 140 mg (33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.C([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)C.Cl.C(N=C=NCCCN(C)C)C.N1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH3:18])[C:13]=3[C:12]([C:19]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Reactant: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c21
Reaction time: 24 h

Procedure:
A solution of 4-[(3-chlorophenyl)amino]-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (25.0 g) in dry dimethylformamide (300 ml), was treated with 1-hydroxybenzotriazole (14.00 g), N-ethylmorpholine (42 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.03 g) and morpholine (14.4 ml) at 23° C. under argon with stirring. After 24 h, the solution was evaporated in vacuo and treated with aqueous saturated sodium carbonate (200 ml) and water (300 ml). The mixture was extracted with ethyl acetate (5×200 ml), and the combined, dried (Na2SO4) organic extracts were evaporated in vacuo. The residue was purified by column chromatography on a Biotage silica column (800 g) eluting with ethyl acetate-hexane (1:1 to 7:3) to give the free base of the title compound (26.9 g). A portion of the free base (21.9 g) in methanol (250 ml) was treated with 1.0M hydrochloric acid in diethyl ether to pH1 and then evaporated in vacuo. Trituration of the residue with ether followed by filtration yielded the title compound (22.75 g).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[C:5]=1[O:17][CH3:18])[CH:2]=C.I([O-])(=O)(=O)=[O:20].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:18][O:17][C:5]1[C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[C:8]([O:11][CH3:12])=[C:9]([CH3:10])[C:4]=1[CH2:1][CH:2]=[O:20]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1c(C)c(OC)c(OC)c(OC)c1OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(CC=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
109 mg of osmium tetroxide were added to a solution of 7.98 of 1-allyl-2,3,4,5-tetramethoxy-6-methylbenzene [prepared as described in step (a) above] in a mixture of 300 ml of dioxane and 100 ml of water, and the resulting mixture was stirred at room temperature for 10 minutes. An aqueous solution of 35.6 g of sodium periodate was then added dropwise, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was freed from the dioxane by evaporation under reduced pressure, and the resulting concentrate was poured into a saturated aqueous solution of sodium chloride, after which it was extracted with diisopropyl ether. The solvent was then removed from the extract by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a gradient elution method with mixtures of hexane and ethyl acetate ranging from 8:1 to 5:1 by volume as the eluent, to give 4.64 g of the title compound.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)=[CH2:9].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>O>[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])=[CH:12][CH:11]=1)=[CH2:9]
Reactant: BrCCCCCCBr
Reactant: C=Cc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(COCCCCCCBr)cc1
Yield: 58 %

Procedure:
A DMF suspension (5 ml) of sodium hydride (50% in oil, 240 mg, 5.0 mmoles) was cooled to 0° C. under an argon atmosphere, and a DMF (1 ml) solution of 1.34 g of 4-vinylbenzyl alcohol (10 mmoles) was added. The reaction mixture was agitated for fifteen minutes, and a DMF solution (3 ml) of 3.66 g of 1,6-dibromohexane (15 mmoles) was added over at least five minutes. The reaction mixture was agitated at room temperature for three hours. Fifteen milliliters of water was added to the reaction solution while cooling using ice, and the solution was agitated for five minutes. The solution was extracted using ethyl acetate (2×40 ml). The combined organic layers were washed using 15 ml of saturated aqueous saline solution and dried using anhydrous sodium sulfate. Upon filtration and concentration, 4.11 g of the residue was purified using silica gel column chromatography (70 g silica gel, 20:1 hexane/Et2O) and 1.72 g of 6-(4-vinylbenzyloxy)bromohexane (5.8 mmoles, 58%) was obtained in the form of an oily substance.