Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].Cl.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1.C([O:18][C:19](=O)[CH:20]([CH3:26])[C:21](OCC)=[O:22])C.Cl>C(O)C>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]2[N:13]=[C:19]([OH:18])[C:20]([CH3:26])=[C:21]([OH:22])[N:12]=2)=[CH:9][CH:8]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(-c2ccc(Cl)cc2)nc1O
Temperature: 40 °C
Reaction time: 44 h

Procedure:
To ethanol (20 ml) was added sodium ethoxide solution (7.76 ml of a 21% wt solution in ethanol), 4-chlorobenzamidine hydrochloride (1.0 g) and diethylmethylmalonate (0.89 ml). The suspension was stirred at 40° C. in an inert atmosphere for 44 hrs after which time it was cooled to 5° C. and treated dropwise with concentrated hydrochloric acid to a pH of 2. The resulting suspension was filtered and washed with excess water, then ethanol (20 ml) and diethyl ether (20 ml) affording the title compound as a solid (1.71 g).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][N:33]1[C:37]([CH:38]=O)=[CH:36][N:35]=[CH:34]1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:37]4[N:33]([CH3:32])[CH:34]=[N:35][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: Cn1cncc1C=O
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4cncn4C)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 1-methyl-1H-imidazole-5-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C:48](=[O:52])[N:47]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[CH2:46]3)=[CH:39][CH:38]=1.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:64]=[C:65]([N:69]=[C:70]=[S:71])[CH:66]=[CH:67][CH:68]=1>>[CH3:59][CH:58]([CH3:60])[C@H:53]([N:47]1[CH2:46][C:45]2[C:49](=[CH:50][CH:51]=[C:43]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:70]([NH:69][C:65]4[CH:66]=[CH:67][CH:68]=[C:63]([C:62]([F:61])([F:72])[F:73])[CH:64]=4)=[S:71])=[CH:38][CH:39]=3)[CH:44]=2)[C:48]1=[O:52])[C:54]([O:56][CH3:57])=[O:55]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 282 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-trifluoromethyl phenyl isothiocyanate. The compound of example 282 was used directly without isolation, for the preparation of compound of example 283.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.Cl.Cl.[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:31][C@@H:29]([C:27]3[O:26][N:25]=[C:24]([CH3:23])[N:28]=3)[CH3:30])=[O:13])=[CH:8][CH:9]=2)[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1ccc(-n2nc(Br)c3ccc(C(=O)O)cc32)cc1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(Br)c3ccc(C(=O)N[C@H](C)c4nc(C)no4)cc32)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
3-Bromo-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid (233.7 mg, 0.389 mmol, with 4 equivalents of sodium chloride), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (94.2 mg, 0.471 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (156.1 mg, 0.814 mmol), 1-hydroxy-7-azabenzotriazole (28.9 mg, 0.212 mmol), and N-methylmorpholine (0.171 mL, 1.554 mmol) were dissolved in N,N-dimethylformamide (3.800 mL) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 10 min. The reaction was stopped, quenched by addition of water (ca 0.5 mL) and trifluoroacetic acid (ca 0.5 mL). The reaction mixture purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water+0.1% trifluoroacetic acid. The product fractions were concentrated under reduced pressure. The residue was taken up in ethyl acetate (15 mL), washed with sodium bicarbonate (2×20 mL) and saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give the title compound (153.9 mg, 0.350 mmol, 90% yield) as a tan solid. HRMS: [M+1]=440.0730.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=[O:7].Cl>O.CO>[O:7]=[C:6]1[NH:5][CH:4]=[CH:3][N:8]1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: COC(CNC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1)OC
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(n2cc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.5 %

Procedure:
Benzyl 4-({[(2,2-dimethoxyethyl)amino]carbonyl}amino)piperidin-1-carboxylate (0.37 g) obtained in Example 16a) was dissolved in water (5 mL) and methanol (10 mL), and 1N hydrochloric acid (5 mL) was added thereto. The mixture was stirred at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.27 g, 90%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=Cc1cccc(Br)n1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
To a chilled (−10° C.) solution of 6-bromopyridine-2-carboxaldehyde (5.0 g, 27 mmol) in THF (108 mL) is added a 1 M solution of 4-fluorophenylmagnesium bromide in THF (30 mL, 30 mmol). The temperature is allowed to slowly warm to room temperature over 30 minutes and then the reaction mixture is quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers are dried over Na2SO4 and concentrated. The crude material is purified by silica gel chromatography eluting with 15% EtOAc-hexanes to afford (6-bromopyridin-2-yl)-(4-fluorophenyl)-methanol.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[CH2:16]([NH:17][CH2:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCCCCCN
Reactant: CCCCCCC1CO1
Solvent: CO
Product: CCCCCCC(O)CNCCCCCCNCC(O)CCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-octene oxide (42 g.) and hexamethylenediamine (19.05 g.) and recrystallization of the resulting product from methanol gave N,N'-(1,6-hexylene)-bis[2-hydroxyoctylamine] (I: R= CH3 (CH2)5, R' = H, X= (CH2)6, Z= H) (17.2 g., m.p. 124.0°-127.4° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7]/[C:8](=[N:11]\[C:12]([C:14]1[N:23]=[C:22]2[N:16]([CH2:17][CH2:18][O:19][C:20]3[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:21]=32)[CH:15]=1)=O)/SC)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[CH:40]([NH:43][NH2:44])([CH3:42])[CH3:41].O>CN(C)C=O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[N:11]=[C:12]([C:14]2[N:23]=[C:22]3[N:16]([CH2:17][CH2:18][O:19][C:20]4[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:21]=43)[CH:15]=2)[N:43]([CH:40]([CH3:42])[CH3:41])[N:44]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS/C(=N/C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Reactant: CC(C)NN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(NC(=O)OC(C)(C)C)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a solution of {[(E)-8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonylimino]-methylthiomethyl}-carbamic acid tert-butyl ester (0.658 g, 0.00137 mol) in N,N-dimethylformamide (7.50 mL) was added N,N-Diisopropylethylamine (0.9524 mL, 0.005468 mol) then isopropylhydrazine hydrochloride (0.2267 g, 0.002050 mol). The reaction was stirred at room temperature for 4 h. Water and methylene chloride were added and the mixture was extracted 3× with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was purified by flash chromatography (0-10% MeOH in DCM) to give [5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamic acid tert-butyl ester (642 mg) a sticky light yellow solid. The material was carried forward without any further purification. MS(ESI+) 489.1/491.1
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH2:13][OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:11][O:12][C:23]([CH3:25])([CH3:24])[O:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CO)(COCc1ccccc1)C1CCCCC1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(COCc2ccccc2)(C2CCCCC2)CO1

Procedure:
2-Benzyloxymethyl-2-cyclohexyl-propan-1,3-diol(3 g.),2,2-dimethoxypropane (8 ml), p-toluenesulphonic acid (150 mg.) and molecular sieves (type 4A) were heated in refluxing dry toluene (50 ml.) for four hours. The mixture was cooled and filtered. The filtrate was diluted with ether and the ethereal solution was extracted with aqueous sodium hydrogen carbonate solution. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with 1:5 ether:hexane. 5-Benzyloxymethyl-5-cyclohexyl-2,2-dimethyl-1,3-dioxane(3.0 g) was obtained as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].S(O)(O)(=O)=O.[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[NH2:29].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]2[N:24]3[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][C:14]([CH3:15])=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: Nc1ncc[nH]1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nccn2C1c1ccc(C#N)cc1
Temperature: 65 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (1.42 g, 5.82 mmol) and 1H-imidazole-2-amine sulfate (2:1) (1000 mg, 3.78 mmol, 0.65 eq.) were dissolved in DMF (10 ml), and solid sodium bicarbonate (1.96 g, 23.3 mmol, 4 eq.) was added. The mixture was stirred at 65° C. for 12 h. The mixture was then filtered through kieselguhr, and the DMF from the filtrate was distilled off under reduced pressure. Acetonitrile (10 ml) was added to the residue. The precipitated product was filtered off, washed with ethanol and dried under high vacuum, which gave a first product fraction (503 mg). The concentrated filtrate was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA) and lyophilized. This gave 778 mg as a further product fraction (total yield: 71% of theory).
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].OC1C=C([C:54]([F:57])([F:56])[F:55])C=CC=1C(O)=O>>[C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([O:28][C:29]1[CH:39]=[C:38]([C:54]([F:57])([F:56])[F:55])[CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1ccccc1C(=O)OCC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Oc1cc(C(F)(F)F)ccc1C(=O)OCC

Procedure:
Ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-4-(trifluoromethyl)benzoate was prepared as described for ethyl 2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate, using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid starting material. Mass calculated for C38H50F3NO5=657.80; found: [M+H]+=658.4.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:40])([CH3:39])[CH2:4][NH:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[CH2:23][CH2:22]3)[N:17]=[C:16]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[N:15]=2)=[C:9]([F:37])[CH:8]=1.[O:41]=[C:42]([N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[C:43](O)=[O:44].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2([NH:20][C:18]3[N:17]=[C:16]([O:31][CH2:32][C:33]([F:35])([F:36])[F:34])[N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][C:3]([CH3:40])([CH3:39])[CH2:2][NH:1][C:43](=[O:44])[C:42](=[O:41])[N:46]5[CH2:50][CH2:49][CH2:48][CH2:47]5)=[O:38])=[CH:8][C:9]=4[F:37])[N:19]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: O=C(O)C(=O)N1CCCC1
Reactant: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)C(=O)N1CCCC1)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a solution of N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide (80 mg, 0.14 mmol) and 2-oxo-2-(pyrrolidin-1-yl)acetic acid (20 mg, 0.137 mmol) in DMF (2 mL) were added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (66 mg, 0.21 mmol) and iPr2NEt (0.050 ml, 0.28 mmol). After stirring at rt for 16 hs, the mixture was purified by preparative HPLC to give 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2,2-dimethyl-3-(2-oxo-2-(pyrrolidin-1-yl)acetamido)propyl)-3-fluorobenzamide (14.4 mg, 14%) as product. 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.01 (6H, s), 1.42 (4H, m), 1.81-2.02 (4H, m), 3.14 (2H, m), 3.29 (2H, d, J=6.0 Hz), 3.60 (2H, t, J=6.9 Hz), 3.91-4.12 (2H, m), 4.70-4.80 (2H, m), 7.14-7.38 (3H, m), 7.48-7.59 (1H, m), 7.69-7.80 (1H, m), 7.94-8.06 (1H, m), 8.24-8.31 (1H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([O:13]C)OC.C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:25][CH2:24][CH2:23][CH:22]=[CH2:21])=[C:3]([CH:4]=1)[CH:10]=[O:13]
Reactant: C=CCCCBr
Reactant: COc1ccc(Br)c(C(OC)OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCc1ccc(OC)cc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Step AH (3): To a solution of 1-bromo-2-(dimethoxymethyl)-4-methoxybenzene (688.5 mg, 2.637 mmol) in THF (7.0 mL) at −78° C. was added n-butyl lithium (3.46 mL, 5.538 mmol). The resulting mixture was stirred at −78° C. for 15 min. 5-Bromopent-1-ene (0.31 mL, 2.637 mmol) was added by drops. The reaction mixture was warmed to rt and stirred overnight. Aqueous hydrochloric acid solution (1N) was added and the reaction mixture was stirred at rt for 3 h. The reaction was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 5-methoxy-2-(pent-4-enyl)benzaldehyde (538.6 mg, 100%) as colorless oil. LC-MS (M+H)+=205.36. 1H NMR (CDCl3, 500 MHz) δ 10.30 (s, 1H) 7.35 (d, J=3.0 Hz, 1H) 7.17 (m, 1H) 7.06 (m, 1H) 5.82 (m, 1H) 5.05-4.98 (m, 2H) 3.84 (s, 3H) 2.12 (m, 2H) 1.69 (m, 2H) 1.57 (m, 2H).
Reaction SMILES: [O:1]([CH:8]([CH3:16])[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[O:1]([CH:8]([CH3:16])[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH2:18][CH2:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(CCBr)cc1
Reactant: CC(CN1CCNCC1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCN2CCN(CC(C)Oc3ccccc3)CC2)cc1

Procedure:
A mixture of 8.2 g. (37 mmole) 1-(2-phenoxypropyl)-piperazine, 9.57 g. (37 mmole) ethyl 4-(2-bromoethyl)-benzoate, 3.77 g. (37 mmole) triethylamine and 100 ml. anhydrous tetrahydrofuran is heated for 36 hours at reflux temperature and then evaporated. The residue is taken up in diethyl ether and the hydrochloride precipitated from this solution with hydrogen chloride-containing diethyl ether to give 14.7 g. (84% of theory) of the desired compound as a hydrochloride; m.p. 232° C.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=2)=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[C:2]#[C:3][CH2:4][CH3:5].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:6][C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=2)=[CH:9][C:10]2[C:11]([CH3:19])([CH3:20])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[C:2]#[C:3][CH2:4][CH3:5]
Reactant: CCC#CCOc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC#CCOc1cc2c(cc1/C=C/c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Yield: 87.9 %

Procedure:
1.30 g of ethyl (E)-4-[2-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoate were placed in 10 ml of abs. ethanol/THF=1/1 and treated under argon with 4.9 ml of 3N NaOH. After 40 h. at room temperature the mixture was poured on to ice and extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl soln., dried and evaporated. Crystallization from hexane/ethyl acetate yielded 1.07 g of (E)-4-[2-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic acid as beige crystals of m.p. 144-145°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl>C(O)C.[Fe]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(N)cc2)cc1Cl
Temperature: 25 °C
Yield: 96.2 %

Procedure:
Iron powder (0.99 g, 17.7 mmol) was added to a solution of methyl 3-chloro-4′-nitrobiphenyl-4-carboxylate (0.64 g, 1.8 mmol) in ethanol (15 mL). Concentrated HCl (0.88 mL, 1.8 mmol) was added, and the mixture was heated at reflux for 3 h. Upon cooling to rt, the mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The material was purified by column chromatography (33% EtOAc in hexanes), yielding 0.453 g (98%) of the title compound. LC/MS m/z 262.4 (Mob; retention time 2.39 min. 1H NMR (400 MHz, CD2Cl2) δ 3.99 (s, 3H), 6.78 (d, 2H), 7.41-7.46 (m, 3H), 7.62 (s, 1H), 7.88 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2O.P(Cl)(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[Cl:19]
Reactant: CS(=O)(=O)c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 100 °C
Yield: 59 %

Procedure:
6-Bromo-3-(methylsulfonyl)quinolin-4-ol (573 mg, 1.90 mmol) was added to phosphoryl chloride (19 mL) and the reaction was stirred at 100° C. 16 h. Additional THF (5 mL) was added and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled and slowly poured into a 2:1 solution of satd. aq sodium bicarbonate/ethyl acetate that was pre-cooled to 0° C. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with satd. aq.sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product (360 mg, 59%) as a white solid: ESI MS m/z 321 [C10H7BrClNO2S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].O1CCCC1.C([Li])(CC)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)[C:8]1=[O:12]
Reactant: COc1cc(CN2CCCC2=O)cc(OC)c1OC
Reactant: Fc1ccc(CBr)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCC(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (0.98 g, 3.70 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyl lithium (2.99 mL, 1.3 M in hexane, 3.88 mmol). After 30 minutes, add 4-fluorobenzyl bromide (0.70 g, 3.70 mmol). After the addition is complete, warm to ambient temperature. After 2 hours, add water and extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate/hexane 1/1 to give the title compound.