Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([C:36]([F:39])([F:38])[F:37])[C:34]=1[Cl:35])[O:5][C@@H:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C@@H:7]([C:11]1[CH:24]=[CH:23][C:14]([C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].[CH3:40][N:41](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[Cl:35][C:34]1[C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:4]([O:5][C@@H:6]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C@@H:7]([C:11]2[CH:24]=[CH:23][C:14]([C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[CH:13][CH:12]=2)[CH2:8][CH2:9][CH3:10])=[CH:3][C:2]=1[C:40]#[N:41]
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](Oc1cc(Br)c(Cl)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](Oc1cc(C#N)c(Cl)c(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
The product from Step B (200 mg, 0.309 mmol), (Ph3P)4Pd (107 mg, 0.093 mmol), and zinc cyanide (54.4 mg, 0.473 mmol) were stirred in DMF (3 mL) at 120° C. for 24 hours. After cooling to RT, the mixture was filtered through celite, then the filtrate was concentrated. The resulting residue was purified by reverse phase HPLC eluting with 60-100% acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the title compound. 1H NMR (500 MHz, (CD3)2CO): δ 7.78 (d, J=8.5 Hz, 2H); 7.62 (d, J=3.0 Hz, 1H); 7.56 (d, 2.5 Hz, 1H); 7.41 (d, J=3.0 Hz, 2H); 7.39 (d, J=2.5 Hz, 2H); 7.34 (d, J=8.5 Hz, 2H); 5.90 (d, J=7.0 Hz, 1H); 3.61 (m, 2H); 3.29 (m, 1H); 2.63 (m, 2H); 2.62-1.77 (m, 1H); 1.62-1.55 (m, 1H); 1.15-1.08 (m, 2H); 0.76 (t, J=7.2 Hz, 3H); LC3 4.09 min. (M+H)+ 593.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C@@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([CH2:15]O)[O:10]2)=[N:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCO.O>[OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:15][C@H:11]3[O:10][C@@H:9]([C:5]2=[N:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12]3
Reactant: CCOC(=O)c1nc([C@@H]2CCC[C@@H](CO)O2)[nH]c(=O)c1O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc2n(c(=O)c1O)C[C@@H]1CCC[C@H]2O1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To ethyl 5-hydroxy-2-((2S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.90 g, 6.37 mmol)in dry THF (60 mL) was added methanesulfonyl chloride (1.49 mL, 19.1 mmol) and di-isopropyl-ethylamine (3.56 mL, 20.0 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 3 h. The THF was removed in vacuo, the crude material was dissolved in ethyl acetate (50 mL) and washed with 1N NaHCO3 (50 mL). The aqueous solution was then washed with ethyl acetate (3×20 mL) and the combined organic fractions were dried (MgSO4) filtered and concentrated in vacuo to give a brown oil. The crude oil was dissolved in EtOH:THF (20 mL:20 mL) and to this was added K2CO3 (0.881 g, 6.37 mmol) and H2O (1.0 mL). The reaction mixture was stirred at 65° C. for 17 h. The solvent was removed in vacuo, the crude material was dissolved in ethyl acetate (50 mL) and washed with H20 (50 mL) and HCl aq. 1N (50 mL). The acidic aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The crude material was purified by preparative HPLC using a C18 column and trifluoroacetic acid in the mobile phase to afford the compound 1.16 g (65% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 10.75 (1 H, s), 4.94 (1 H, d, J=2.3 Hz), 4.49-4.58 (3 H, m), 4.01-4.13 (2 H, m), 2.05-2.17 (2 H, m,), 1.96 (1 H, dd, J=13.6, 2.0 Hz), 1.76 (2 H, m), 1.39-1.49 (4 H, m). LCMS (+ESI, M+H+) m/z 281. HRMS (ESI+) calculated for C13H16N2O5 [M+H+] :281.1137; found: 281.1147.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[C:49]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([O:70][CH3:71])[CH:65]=2)=[C:50]([CH3:63])[C:51]([C:61]#[N:62])=[C:52]2[C:56]=1[O:55][C:54]([C:57]([CH3:60])([CH3:59])[CH3:58])=[N:53]2.[CH3:72][N:73]([CH3:79])[C@H:74]1[CH2:78][CH2:77][NH:76][CH2:75]1.CC(C)([O-])C.[Na+].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:57]([C:54]1[O:55][C:56]2[C:52](=[C:51]([C:61]#[N:62])[C:50]([CH3:63])=[C:49]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([O:70][CH3:71])[CH:65]=3)[C:48]=2[N:76]2[CH2:77][CH2:78][C@H:74]([N:73]([CH3:79])[CH3:72])[CH2:75]2)[N:53]=1)([CH3:60])([CH3:59])[CH3:58]
Reactant: COc1cccc(-c2c(C)c(C#N)c3nc(C(C)(C)C)oc3c2Br)c1
Reactant: CN(C)[C@H]1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(-c2c(C)c(C#N)c3nc(C(C)(C)C)oc3c2N2CC[C@H](N(C)C)C2)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 2.2 %

Procedure:
(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (70.2 mg, 113 μmol) was dissolved in toluene (2.7 ml) under heat, cooled to room temperature, then palladium(II) acetate (16.9 mg, 75.1 μmol) was added followed by stirring for 1 minute. 7-Bromo-2-tert-butyl-6-(3-methoxyphenyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-20) (300 mg, 751 μmol), (3S)-3-(dimethylamino)pyrrolidine (114 μl, 902 μmol), sodium tert-butoxide (101 mg, 1.05 mmol), toluene (2.7 ml) were successively put into it, followed by stirring at 80° C. for 16 hours. After cooling, saturated sodium bicarbonate water (50 ml) was added to the reaction liquid, the product was extracted with chloroform (50 ml×2). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1), then further purified by silica gel thin-layer partitioning (chloroform:methanol:acetic acid=80:10:5) to obtain the entitled compound (7.3 mg, 2.2%) as a yellow semi-solid.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
A pyridine suspension (40 ml) containing 2-amino-5-nitropyridine (4.0 g) and p-toluenesulfonyl chloride (5.7 g) was stirred for a day and night at 100° C. The reaction liquid was poured in water (200 ml), the precipitated solid was recovered by filtration, and successively washed with water and diethyl ether by the order stated. Drying the solid under reduced pressure, 4-methyl-N-(5-nitro-2-pyridinyl)benzenesulfonamide (6.7 g) was obtained.
Reaction SMILES: [CH3:1][CH2:2][C@H:3](O)[CH2:4][CH2:5][C@@H:6](O)[CH2:7][CH3:8].[PH2:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[PH2:21]>>[CH2:2]([C@@H:3]1[CH2:4][CH2:5][C@@H:6]([CH2:7][CH3:8])[P:11]1[C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[P:21]1[C@H:6]([CH2:7][CH3:8])[CH2:5][CH2:4][C@H:3]1[CH2:2][CH3:1])[CH3:1]
Reactant: CC[C@H](O)CC[C@@H](O)CC
Reactant: Pc1sc2ccccc2c1P
Product: CC[C@@H]1CC[C@@H](CC)P1c1sc2ccccc2c1P1[C@H](CC)CC[C@H]1CC
Yield: 48 %

Procedure:
In analogy to Example 11, the cyclic sulfate derived from (3S,6S)-3,6-octanediol is reacted with 2,3-bisphosphinobenzo[b]thiophene to give the title compound in 48% yield.
Reaction SMILES: C(NC([NH:8][CH2:9][C:10]#[C:11][CH2:12][NH:13][C:14]([NH:16][C:17]1[S:18][C:19]2[C:25]3[N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[CH:28][C:24]=3[CH2:23][CH2:22][C:20]=2[N:21]=1)=[O:15])=O)(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]#[C:11][CH2:12][NH:13][C:14]([NH:16][C:17]1[S:18][C:19]2[C:25]3[N:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:27]=[CH:28][C:24]=3[CH2:23][CH2:22][C:20]=2[N:21]=1)=[O:15]
Reactant: CC(C)(C)NC(=O)NCC#CCNC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccccc1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#CCNC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccccc1)CC2

Procedure:
0.1 g (0.2 mmol) of the compound obtained in Example 11 are suspended in 0.5 ml trifluoroacetic acid and 2 ml dichloromethane and stirred overnight at ambient temperature. The reaction mixture is evaporated down, the residue taken up in acetone and the product is precipitated by the addition of ethereal hydrochloric acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[C:44]([O:45][CH3:46])=[CH:43][CH:42]=[CH:41][C:38]=1[CH:39]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[C:44]([O:45][CH3:46])=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1OCc1ccccc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-benzyloxy-3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 605.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:12][N:11]3[CH:24]=2)=[CH:4][CH:3]=1.[I:25]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)=[N:12][N:11]3[C:24]=2[I:25])=[CH:6][CH:7]=1
Reactant: Cc1c(N2CCNCC2)nn2cc(-c3ccc(F)cc3)nc2c1C
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(N2CCNCC2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution, cooled to 0° C., of 1.15 g (3.53 mmol) of 2-(4-fluorophenyl)-7,8-dimethyl-6-piperazin-1-ylimidazo[1,2-b]pyridazine in 20 mL of dichloromethane, is added dropwise a solution of 2.29 g (14.1 mmol) of iodine monochloride in 5 mL of methanol and the medium is stirred for 30 minutes at room temperature. 5% sodium thiosulfate solution is then added and the medium is basified by addition of sodium hydrogen carbonate.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[C:13]([F:16])=[N:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[N+]1([O-])CCOCC1.C(Cl)Cl>C1COCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:16][C:13]1[C:12]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[CH:21][CH:22]=2)=[CH:11][C:10]([CH:9]=[O:8])=[CH:15][N:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(F)c(-c2ccc(OCC(F)(F)F)nc2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cnc(F)c(-c2ccc(OCC(F)(F)F)nc2)c1
Reaction time: 4 h

Procedure:
5-((tert-Butyldimethylsilyloxy)methyl)-2-fluoro-3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyridine (0.204 g, 0.490 mmol) was placed into a flask with 5.0 mL of tetra-butylammonium fluoride in THF and stirred for 4 h. The reaction was then quenched by adding water (5 mL) and extracting with EtOAc (3×5 mL). The combined organic layers were then washed with brine (1×5 mL), dried (MgSO4), filtered, and concentrated. The resulting crude oil (0.145 g, 0.480 mmol) was then placed into a flame-dried flask, and to the reaction mixture was added N-methylmorpholine N-oxide (0.169 g, 1.44 mmol), 4 Å molecular sieves (10 mg), and CH2Cl2 (1.0 mL). Tetrapropylammonium perruthenate (8.43 mg, 0.024 mmol) was then added, and the suspension was stirred at rt overnight. The reaction mixture was worked-up by filtering through Celite® and concentrating the filtrate to give 6-fluoro-5-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)nicotinaldehyde.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([CH:39]4[CH2:41][CH2:40]4)=[CH:34][N:33]=3)[CH2:28][CH2:27]2)=[O:25])=[C:20]([F:42])[CH:19]=1>>[CH:39]1([C:35]2[CH:36]=[C:37]([CH3:38])[C:32]([N:29]3[CH2:28][CH2:27][N:26]([C:24]([C:21]4[CH:22]=[CH:23][C:18]([N:11]5[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]5(=[O:15])=[O:16])=[CH:19][C:20]=4[F:42])=[O:25])[CH2:31][CH2:30]3)=[N:33][CH:34]=2)[CH2:40][CH2:41]1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3[C@H](CO)CCS3(=O)=O)cc2F)CC1
Yield: 10 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (241 mg) described in Preparation Example 1 and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 32, the title compound (49 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[C:11]3[CH:22]=[C:23]([C:25]([OH:27])=O)[S:24][C:10]=3[C:9]=2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:4][CH:3]=1.CN.C[CH2:37][N:38](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])[C:11]3[CH:22]=[C:23]([C:25]([NH:38][CH3:37])=[O:27])[S:24][C:10]=3[C:9]=2[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution (0.02 M) of 5-(4-chlorophenyl)-6-cyclohexyl-4-(2-morpholin-4-yl-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in DCM at RT was treated with methylamine (2 N solution in THF, 1.5 eq.), DIEA (3 eq.) and HATU (2 eq.). The mixture was stirred at RT for 2 h, then it was diluted with DCM and washed sequentially with aqueous HCl (0.1 N), aqueous NaHCO3 (saturated solution) and dried. Evaporation of the solvent under reduced pressure gave a residue which was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×100 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 50% A isocratic for 1 min then linear to 20% A in 9 min) to afford the title compound (74%) as a solid.
Reaction SMILES: CS(C)=O.[H-].[Na+].[SH:7][CH2:8][CH2:9][OH:10].Br[CH2:12][CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O>[OH:10][CH2:9][CH2:8][S:7][CH2:12][CH2:13][C:14]([CH3:21])([CH3:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(C)(C)CCBr
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(C)(C)CCSCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 50 ml. dimethyl sulphoxide and 42.2 mmol sodium hydride is maintained at 80° C. for 45 minutes. It is then cooled to ambient temperature, 3.3 g. (42,2 mmol) 2-mercaptoethanol and then 10.0 g. (42,2 mmol) ethyl 5-bromo-3,3-dimethylpentanoate are added thereto and the reaction mixture is stirred for 3 hours at ambient temperature. It is then poured into water and extracted with diethyl ether. The ethereal phase is dried with anhydrous sodium sulphate and then evaporated. After chromatography of the residue on silica gel with a mixture of equal parts by volume of diethyl ether and cyclohexane, there are obtained 6.8 g. (70% of theory) of the desired product in the form of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH3:10])[N:5]=[C:4]([C:11]([O:13][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[O:12])[CH:3]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCn1nc(C(=O)O)cc(N)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nc(C(=O)OCC(=O)OCc2ccccc2)cc(N)c1=O
Temperature: 50 °C
Yield: 91.5 %

Procedure:
5-Amino-1-ethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (0.6 g, 3.3 mmol, see Preparation 5), benzyl bromoacetate (1.6 ml, 4.8 mmol), and potassium carbonate (0.5 g, 3.3 mmol) were suspended in dimethylformamide (30 ml) and heated overnight at 50° C. The solvent was evaporated under reduced pressure and the residue was passed through a silica-gel column, eluting with hexane/ethyl acetate 3:2, to yield 1.0 g of the desired final product. Yield=92%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:28][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]2[CH3:21])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CC1CCCCC1N
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCCCC2C)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 20.0 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 100 ml of abs. DMF was added 27.8 g of potassium carbonate, followed by 12.5 g of 2-methylcyclohexylamine. After 16 h at rt, the mixture was poured into water, the pH was adjusted to 4 by the addition of 2 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 29.4 g (100%) of 4-(2-Methyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester. C15H20N2O4 (292.34), LCMS (method 7—1—1): Rt=1.85 min, m/z=293.25 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([OH:26])([CH3:25])[C:22]([OH:24])=O)[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C:21]([OH:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:44])([F:36])[C:40]([F:43])([F:42])[F:41])=[O:24])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-hydroxy-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoro-propylamine, the title compound was prepared in the same manner as example 1c (59%). White solid. MS: m/e=606(M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=[O:3])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C)C=O>[C:1]([C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:28])[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1cc(CO)c(OCCCCC#N)cc1OCCCCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(C(C)=O)c(OCCCCC#N)cc1OCCCCC#N
Reaction time: 8 h

Procedure:
A mixture of 688 mg of 5,5'-[(4-acetyl-6-hydroxymethyl-1,3-phenylene)bis(oxy)]bis[pentanenitrile] in 15 ml of dimethylformamide was added to a suspension of 0.184 g of a 50% oil dispersion of sodium hydride and 0.62 ml of methyl iodide in 45 ml of dimethylformamide at 0° C. The reaction was allowed to come to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid to which sodium chloride had been added. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by high pressure liquid chromatography over silica gel eluting with a 0-70% ethyl acetate in hexane gradient to provide 110 mg of the desired title product. NMR, MS.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>O1CCCC1.C(OCC)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: OCCCCCCCCCCCc1ccc(O)cc1
Reactant: C=CC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCCCCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
2.5 ml of acryloylchloride was added to a solution of 7.4 g of 4-(11-hydroxyundecyl)-phenol (D) and 3.9 ml of N,N-dimethylaniline in 60 ml of tetrahydrofuran, cooled in an ice bath. After stirring for three hours at room temperature, the solution was diluted with 60 ml of diethyl ether and extracted subsequently with 100 ml of water, 100 ml of 2.4 N HCl and 100 ml of a saturated NaCl solution. 4.74 g of 4-(11-acryloyloxyundecyl)phenol (G, 53%) was obtained as a brown powder after drying over magnesium sulphate, evaporating and washing with ligroin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1Cc2ccccc2CN1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1Cc2ccccc2CN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.