Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[OH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH2:16]1.N1CCCCC1>ClCCCC>[OH:24][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:14])[C:16]1=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N:3]([CH2:12][CH3:13])[CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: O=C1CC(O)c2ccccc21
Solvent: CCCCCl
Solvent: C1CCNCC1
Product: CCN(CC)c1ccc(C=C2C(=O)c3ccccc3C2O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
A mixture of 56.6 g.(0.32 mole) of p-diethylaminobenzaldehyde, 47.36 g. (0.32 mole) of 3-hydroxy-1-indanone and 7 ml. of piperidine was then heated with magnetic stirring to 80°-100° C. for 1.5 hours (the mixture is a melt at the reaction temperature). The mixture was cooled in ice water, 90 ml. of 1-chlorobutane and seed was added. The product tended to come out as a gum; the solution was therefore heated, cooled (seeded) and muddy brown solid separated. The product was collected by filtration and the brown solid washed until bright orange; 43.62 g. 44% yield, m.p. 139°-141°, m.p. recrystallized material (1-chlorobutane) 142°-143° C. An extra 11% yield was obtained through concentration and refiltration of the filtrate; the latter fraction washed up as cleanly as the first. The IR spectrum and elemental analysis are those expected of the titled merocyanine derivative.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)(=O)=O)[N:25]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:34]>CO>[NH2:34][C:26]1[N:25]=[C:24]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[CH:29]=[CH:28][N:27]=1
Reactant: N
Reactant: COc1ccc(C2(C#Cc3ccnc(S(C)(=O)=O)n3)CCC(=O)CC2)cc1OC1CCCC1
Solvent: CO
Product: COc1ccc(C2(C#Cc3ccnc(N)n3)CCC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
Into a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-methylsulfonylpyrimidin-4-ylethynyl)cyclohexan-1-one (0.26 g, 0.56 mmol) in methanol (4 mL) at -78° C. was condensed liquid ammonia (4 mL), the pressure tube was sealed and the reaction was stirred at room temperature for 2.5 h. After cooling, the solvents were evaporated. Purification required two flash chromatographies, eluting first with 2:98 methanol:dichloromethane and secondly with 4:6 ethyl acetate:hexanes, to provide 4-(2-aminopyrimidin-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as a white solid (0.18 g, 73%), mp 68°-70° C. Anal. (C24H27N3O3.0.2 H2O) calcd: C, 70.46; H, 6.75; N, 10.27; found: C, 70.73; H, 6.79; N, 9.87.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[NH:67]1[CH2:72][CH2:71][CH:70]([O:73][C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([O:73][CH:70]4[CH2:71][CH2:72][NH:67][CH2:68][CH2:69]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(OC2CCNCC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(OC4CCNCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 24 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(piperidin-4-yloxy)benzaldehyde (1.2 eq, 0.091 mmol, 22 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (10 mg, 24%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.77-1.81 (m, 2H, 2× piperidine CHAHB), 2.09-2.11 (m, 2H, 2× piperidine CHAHB), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.00-3.07 (m, 2H, 2× piperidine CHAHB), 3.20-3.24 (m, 2H, 2× piperidine CHAHB), 3.62 (s, 2H, NCH2), 3.66 (s, br, 4H, piperazine N(CH2)2), 4.70-4.76 (m, 1H, piperidine CH), 7.15 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.6, 4.7 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.8 Hz, pyridine H-4), 8.13 (d, J=8.7 Hz, 2H, phenyl H-2 & H-6), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.4 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2), 13.42 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[Cl:32][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][C:18]1[C:17]2[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:14]([O:33][CH3:34])=[CH:15][CH:16]=2)[O:21][C:20](=[O:23])[CH:19]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN1CCCC1

Procedure:
The title compound was prepared from pyrrolidine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.58 (br s, 1H), 8.50 (s, 2H), 7.83 (d, 1H), 7.02 (d, 1H), 4.12 (br s, 1H), 3.97 (t, 2H), 3.87 (s, 3H), 2.87 (br, 6H), 1.80 (m, 4H), 1.70 (m, 4H), 1.53 (m, 2H); MS (ESI): 491.9.
Reaction SMILES: CC(OC([NH:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(C)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(C)ccc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-methyl-2-pyridinecarboxylate D34 (1.3 g) was dissolved in DCM (80 ml) and the mixture stirred at 0° C. A solution of TFA (5 ml, 64.9 mmol) in DCM (10 ml) was dropped into the cold mixture over 3 minutes. The resulting solution was left under stirring at 0° C. for 30 minutes, then the mixture was left still at room temperature overnight. TFA (4 ml, 51.9 mmol) dissolved in DCM (10 ml) was added over 3 minutes and the mixture stirred again at room temperature for 5 hours. The solution was loaded onto an SCX-25 g column, the column was eluted and after evaporation under reduced pressure of the solvent it was obtained the title compound D35 (770 mg) was obtained as a white solid. UPLC (Basic GEN_QC): rt=0.44 minutes, peak observed: 167 (M+1). C8H10N2O2 requires 166. 1H NMR (400 MHz, CDCl3) δ ppm 7.14 (d, 1 H), 7.01 (d, 1 H), 3.99 (s, 3 H), 2.52 (s, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=1)[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14].P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[S:13]([Cl:12])(=[O:15])=[O:14])[CH3:2]
Reactant: CCc1cc2cccnc2s1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1sc2ncccc2c1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.3 %

Procedure:
To a solution of 2-ethylthieno[2,3-b]pyridine (0.43 g, 2.6 mmoles) in CH2Cl2 (10 ml) at -78° C. was added chlorosulfonic acid (0.9 ml, 13 mmoles). The reaction was warmed to ambient temperature over a 1 hr. period, then stirred an additional 20 hrs., followed by the addition of phosphorus oxychloride (1.7 ml, 18 mmoles) and phosphorus pentachloride (0.82 g, 4.0 mmoles). One hour later the reaction mixture was added to ice (100 ml) and extracted with EtOAc (75 ml), then washed with sat. NaHCO3 (200 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect a brown oil. Flash chromatography (10% EtOAc/hexanes) provided 0.39 g (56%) of the title compound as a light yellow oil.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:12][NH:11][CH2:10]1)(C(C)(C)C)(C)C.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)[CH2:15][CH2:14]1.CC([O-])(C)C.[Na+].O1CCOCC1>O>[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:11]3[CH2:10][CH:9]([OH:8])[CH2:12]3)=[CH:20][CH:19]=2)[CH2:14][CH2:15]1
Reactant: Ic1ccc(OCC2CC2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OC1CN(c2ccc(OCC3CC3)cc2)C1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
6.50 g (26.0 mmol) 3-(tert-butyldimethylsilyloxy)azetidine, 7.13 g (26.0 mmol) of 1-(cyclopropylmethoxy)-4-iodobenzene (WO2012/028676), 10.0 g (104 mmol) NaOtBu and 1.54 g (2.08 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2-(2-aminoethyl)-phenyl)-palladium (II) are added to 65 mL dioxane and stirred at 75° C. for 2.5 h under inert gas atmosphere. Water is added and the resulting mixture is extracted with EtOAc. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo. The resulting crude product is purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([OH:28])[CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:46]I.O>C1COCC1>[CH:29]1([C:26]([C:16]2[CH:17]=[C:18]([CH3:25])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)([O:28][CH3:46])[CH3:27])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cc(C(C)(O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(c1cc(C)c(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol (18 mg, 0.028 mmol) in THF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 8 mg, 0.202 mmol) at room temperature. After stirring for 5 minutes methyl iodide (12.2 mg, 0.086 mmol) was added and the solution was stirred at room temperature for 18 hours. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The organics were combined, dried with anhydrous sodium sulfate, filtered and concentrated to give an oil (17 mg). This material was purified by flash chromatography on a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10% ethyl acetate in heptane) to yield the title compound (11 mg, 59%). 1H NMR (400 MHz, CDCl3) δ7.75 (s, 1H) 7.70 (s, 2H) 7.39 (s, 1H) 7.01 (s, 1H) 5.19 (d, J=17.42 Hz, 1H) 5.0 (d, J=17.42 Hz, 1H) 4.74 (q, J=16.72 Hz, J=16.18 Hz, 2H) 4.17 (s, 3H) 3.0 (s, 3H) 2.42 (s, 3H) 1.99 (d, J=12.40 Hz, 1H) 1.72 (m, 2H) 1.58 (s, 3H) 0.99 (m, 8H). MS calc. 637.5, found 638.5 (M+H)
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25]>CN(C=O)C>[C:28]([O:27][C:23]([NH:24][NH:25][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=1[F:10])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
N,N-Diisopropylethylamine (14.1 ml, 0.081 mol) is added to 2-fluoro-4-nitrobenzoic acid (5 g, 0.027 mol) and O-(7-azabenzotriazol-1-yl)-N,N, N,N′-tetramethyluronium hexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml) and the mixture stirred at room temperature for 20 minutes. tert-Butyl carbazate (3.57 g, 0.0270 mol) is added in one portion and the reaction stirred overnight at room temperature. The mixture is concentrated and diluted with water (100 ml). The resulting precipitate is filtered, washed well with water, and dried under vacuum to give the title compound as a white solid (4.63 g, 57%), [M+H]+=300.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](Cl)=[O:5].I.[CH3:8][N:9]([C:18]([S:20][CH3:21])=[NH:19])[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C.ClCCl>[CH3:1][S:2][CH2:3][C:4]([N:19]=[C:18]([N:9]([CH3:8])[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:20][CH3:21])=[O:5]
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Reactant: CSCC(=O)Cl
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCC(=O)N=C(SC)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
(Methylthio)acetyl chloride (5.6 g) was added portionwise to a solution of methyl 1-methyl-2-(phenylmethylene)hydrazine carboximidothioate hydroiodide (A) (10.4 g) in triethylamine (7.08 g) and dichloromethane (55 ml) and the mixture stirred at room temperature for 2 h. The mixture was washed with water and evaporated to give an oil which was chromatographed using 1:1 ether-petroleum ether (b.p. 60°-80°) followed by ether to give the title compound (4.6 g) as a cream solid, m.p. 68°-70°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][C:9]([CH2:10][C@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:12]([OH:31])[CH2:13][N:14]([S:19]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.[O:46]1[CH:50]=[CH:49][C:48]([C:51](O)=[O:52])=[CH:47]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([S:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][C@@H:12]([OH:31])[C@@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:10][C:9]3[CH:44]=[CH:45][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:51]([C:48]4[CH:49]=[CH:50][O:46][CH:47]=4)=[O:52])=[CH:7][CH:8]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccoc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCNC(=O)c2ccoc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A solution of 44 mg (0.068 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(3-aminopropoxy)benzyl]-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 15 mg (0.14 mmol) of 3-furoic acid, and 36 μL (0.20 mmol) of N,N-diisopropylethylamine in 2 mL of anhydrous DMF was treated with 52 mg (0.14 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and the resulting solution was stirred at RT. After 18 hours the solution was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, 97:3 CH2Cl2/MeOH) to afford 38 mg (75%) of the desired compound as a white foam. 1H NMR (CDCl3): 7.88 (s, 1H), 7.38 (s, 1H), 7.29 (d, 1H) t 7.10 (m, 3H), 6.84 (d, 1H), 6.76 (d, 2H), 6.56 (s, 1H), 6.34 (br s, 1H), 6.05 (s, 2H), 5.60 (d, 1H), 5.00 (m, 2H), 4.01 (t, 2H), 3.90 (dd, 1H), 3.80 (m, 3H), 3.64 (m, 2H), 3.55 (q, 2H), 3.17-2.63 (m, 8H), 2.03 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.49 (m, 1H), 0.89 (d, 3H), 0.83 (d, 3H). MS(ESI): 744(M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH:23]C(=O)C>>[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH2:23]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Temperature: -20 °C
Yield: 5 %

Procedure:
A mixture of concentrated nitric acid (0.49 mL) and concentrated sulfuric acid (3.9 mL) was cooled to −20° C. and 2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (2.10 g, 8.04 mmol) was added portionwise. The mixture was allowed to warm slowly to r.t. and was then heated to 45° C. for 30 min. The mixture was poured onto ice and the white precipitate was filtered off. The white solid was then dissolved in MeOH (8 mL) and this solution was treated with sulfuric acid (0.8 mL) and heated to reflux for 45 min. The mixture was concentrated in vacuo and was then taken up in EtOAc, washed twice with aqueous potassium hydrogencarbonate, once with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 60, toluene/EtOAc 96:4) affording pale yellow crystals that were recrystallized in EtOAc to provide 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester (116 mg, 0.44 mmol, 5%) as a white solid, m.p. 175-177° C., 1H-NMR (DMSO-d6, 400 MHz) 8.59 (s, 1H), 8.04 (br s, 2H), 7.40 (s, 1H), 3.88 (s, 3H).
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8]CC)=O)=O.C1(C)C=CC=CC=1.Cl.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][NH2:31]>C(O)(=O)C>[OH:8][C:6]1[N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[N:31]=[C:3]([C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=1
Reactant: Cc1ccccc1NN
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(O)n(-c2ccccc2C)n1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
To a mixture of diethyl oxalacetate sodium salt (10.5 g, 50 mmol), acetic acid (100 mL) and toluene (50 mL) was added an aqueous solution (50 mL) of (2-methylphenyl)hydrazine hydrochloride (7.93 g, 50 mmol) under stirring at room temperature, and the mixture was heated under reflux for 3 hr. After cooling, the reaction mixture was partitioned. The organic layer was washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give yellow crystals. This product was dissolved in acetic acid (36 mL), and the mixture was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and recrystallized from hexane-ethyl acetate to give the title compound (2.69 g, yield 22%) as colorless crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](O)=[O:19])=[CH:12][CH:11]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:18](=[O:19])[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: OCCCCCCBr
Reactant: O=C(O)CCc1ccc(O)cc1
Product: O=C(CCc1ccc(O)cc1)OCCCCCCBr
Yield: 70 %

Procedure:
From 6-bromo-1-hexanol and 3-(4-hydroxyphenyl)propionic acid. Working up by means of distillation. Yield: 70%. Boiling point: 205° C. (0.05 mbar).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].NC1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Br:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[C:31]([I+]C1C=CC=CC=1)=[C:30]2[OH:45]>>[Br:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[C:31]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[C:30]2[OH:45]
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1[I+]c1ccccc1
Reactant: CC(C)Nc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Nc1ccccc1
Product: CC(C)N(c1ccccc1)c1c(O)c2cc(Br)ccc2[nH]c1=O

Procedure:
The title compound was prepared using N-isopropylaniline at 50° C. in place of aniline at room temperature according to the procedure of Intermediate 11, step c except the crude solid was purified by flash column chromatography (silica gel, 50% EtOAc-Heptane), affording the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]1([O:24][C:25]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=2[C:27](O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:27]([C:26]3[CH:30]=[C:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=[CH:33][C:25]=3[O:24][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:28])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 (b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with concentrated sulfuric acid (5 drops). The resulting reaction mixture was heated under reflux for 67 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (300 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e calcd for C15H19IO2 (M+) 358.0430, found 358.0434.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)(Cl)Cl)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[OH:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:31]2[O:32][C:9]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[O:20][C:21]=2[CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: Clc1cc(Cl)cc(C(Cl)(Cl)c2cc(Cl)cc(Cl)c2)c1
Product: CCOC(=O)c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2

Procedure:
This compound was prepared from bis-(3,5-dichlorophenyl)dichloromethane and ethyl 3,4-dihydroxybenzoate according to Example 269d; light red solid, m.p.: 89° C.;