Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])[CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][N:11]=1)=[O:8])([O-])=O.C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH3:31])[CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][N:11]=1)=[O:8]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCCc3scnc3C)cc([N+](=O)[O-])c2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ncsc1CCOc1cc(N)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reaction time: 18 h
Yield: 45.5 %

Procedure:
10% Palladium on carbon (0.20 g) was added under an argon atmosphere to a solution of methyl 2-[3-nitro-5-(4-methyl-thiazol-5-yl) ethoxy benzoyl]amino-5-pyridine carboxylate (1.05 g, 1.7 mM) in ethyl acetate (50 ml)/ethanol (50 ml). Hydrogen gas was introduced and the reaction mixture stirred vigorously for 18 hrs before filtering through diatomaceous earth, concentration in vacuo and replacement of the catalyst (80 mg). After stirring under hydrogen gas for a further 18 hrs a final catalyst change was carried out, after which the crude aniline was purified on silica gel (1% to 4% MeOH/DCM) to give the title compound as a colourless solid (0.43 g, 60%); 1H NMR δ (d6-DMSO): 2.36 (s, 3H), 3.18 (dd, 2H), 3.88 (s, 3H), 4.12 (dd, 2H), 5.32 (bs, 2H), 6.33 (m, 1H), 6.79 (m, 2H), 8.30 (m, 2H), 8.81 (s, 1H), 8.88 (m, 1H), 10.90 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[NH:5][CH2:6][CH2:7][CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=O.B>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:11]([CH3:13])[CH3:12])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: CN(C)C(=O)CCCNc1ccc(Cl)c(Cl)c1
Agent: B
Product: CN(C)CCCCNc1ccc(Cl)c(Cl)c1

Procedure:
In the manner given in Example 24, 4-(3',4'-dichloroanilino)-N,N-dimethylbutyramide is reduced with borane in tetrahydrofuarn to give N-(3',4'-dichlorophenyl)-N',N'-dimethylbutane-1,4-diamine as an oil.
Reaction SMILES: [K+].[C:2]1(=[O:17])[N:6]([CH2:7][S:8]([O-])(=[O:10])=[O:9])[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:3]12.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[C:2]1(=[O:17])[N:6]([CH2:7][S:8]([Cl:19])(=[O:10])=[O:9])[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:3]12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1CS(=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CS(=O)(=O)Cl
Reaction time: 1.5 h

Procedure:
To 41.7 g. (0.15 mol.) of phthalimidomethanesulfonic acid potassium salt in 220 ml. of dry benzene is added 22.5 g. (0.132 mol.) of phosphorus pentachloride. The reaction mixture is refluxed on a steam bath for one hour, then an additional 22.5 g. of phosphorus pentachloride is added and heating is continued for 1.5 hours. The reaction mixture is evaporated to dryness, crushed ice is added to the residue and the slurry is filtered. The product is washed with water to give phthalimidomethanesulfonyl chloride.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=1.N>>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Clc1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-chloro-3-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.46 (s, 1H), 7.49-7.55 (m, 2 H), 7.60 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.82-7.90 (m, 1H), 7.93-8.00 (m, 1H), 8.37 (dt, J=7.9, 2.0 Hz, 1H), 8.67 (dd, J=5.1, 1.7 Hz, 1H), 9.09 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 257 (M+H)+.
Reaction SMILES: [CH:1]([O-:3])=O.[Rb+].C[Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8]>>[CH3:8][O:7][Si:6]([O:3][CH3:1])([O:11][CH3:12])[O:9][CH3:10]
Reactant: O=C[O-]
Reactant: CO[Si](C)(OC)OC
Agent: [Rb+]
Product: CO[Si](OC)(OC)OC
Reaction time: 4 h
Yield: 94292.9 %

Procedure:
Example 2 was repeated except that 0.04 gram of rubidium formate was used as the alkali carboxylate catalyst component and reaction time was 4.0 hours. Under these conditions 5.2 grams of methyltrimethoxysilane; 44.0 grams of tetramethoxysilane were produced; and 14.0 grams of methanol was unreacted. Of the total organosilanes in the distillation product 10.5 percent was methyltrimethoxysilane.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3cc(F)ccc3F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1cc(F)ccc1F

Procedure:
The 2-trifluoroacetamido-3-(2,5-difluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (12.1 g, 27.1 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 6.10 g. (64.6%) EA, MS (FD).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1O
Yield: 88.6 %

Procedure:
A mixture of 4-chloro-2-hydroxybenzoic acid (200 g, 1.16 mol) and 40 ml conc. sulfuric acid in 400 ml of methanol was heated under reflux for 201/2 hours. The solvent was evaporated under reduced pressure, the residue poured into aqueous saturated Na2CO3, and then extracted with ethyl ether (3×500 ml). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to give 2f (191.6 g, 88.6% yield) as an oil. This was used for the next reaction without purification. IR (neat) 3150 (OH), 1728 (C=0), and 1678 (C=0) cm-1. NMR (CDCl3) δ 10.27 (br s, 1H, OH), 7.47 (d, 1H, JBC =8 Hz, HC), 6.80 (d, 1H, JAB =2 Hz, HA), 6.63 (d of d, 1H, HB), and 3.85 (s, 3H, CH3).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Reactant: O=C=Nc1ccccc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 145, 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.05 mmol) was reacted with phenyl isocyanate to provide 0.45 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}-N′-phenylurea as a white powder, m.p. 125.0-130.0° C. Analysis: Calculated for C25H30N6O2.0.40 H2O: % C, 66.18; % H, 6.84; % N, 18.52. Found: % C, 66.05; % H, 6.61; % N, 18.64. % H2O calculated: 1.59. found: 1.53 (Karl Fisher);
Reaction SMILES: [Cl-:1].[NH:2]([C:4](=[O:12])[CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:3].[CH:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH:21]=O)=[CH:15][CH:14]=1>C(O)C>[Cl-:1].[O:12]=[C:4]([NH:2]/[N:3]=[CH:21]/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)[CH2:5][N+:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=O)C[n+]1ccccc1
Reactant: O=C/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: O=C(C[n+]1ccccc1)N/N=C/C=C/c1ccccc1
Temperature: 25 °C
Yield: 21.1 %

Procedure:
A mixture of 4a (1.5 g, 8.0 mmol) and trans cinnamic aldehyde (1.6 g, 12.0 mmol) in ethanol (20 ml) was heated under reflux for 3 h. After cooling to room temperature, the mixture was filtered, and the residue dried under vacuum (0.6 mbar) to give 0.51 g (21%) of a pale-yellow solid consisting of two isomers with respect to the amide bond conformation (E:Z ca. 3:1).
Reaction SMILES: [C:1]([C:6]1[S:13][C:12]2[C:11]3[S:14][C:15]4[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CCCCCCC)=[C:18]([C:37]([O:39]CC)=[O:38])[S:17][C:16]=4[C:10]=3[S:9][C:8]=2[C:7]=1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]CCCCCCC)([O:3]CC)=[O:2].CO.[OH-].[Li+]>O1CCCC1.O>[CH2:20]([C:19]1[C:15]2[S:14][C:11]3[C:12]4[S:13][C:6]([C:1]([OH:3])=[O:2])=[C:7]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:8]=4[S:9][C:10]=3[C:16]=2[S:17][C:18]=1[C:37]([OH:39])=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCc1c(C(=O)OCC)sc2c1sc1c3sc(C(=O)OCC)c(CCCCCCCCCCCCCCCCC)c3sc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c3sc(C(=O)O)c(CCCCCCCCCC)c3sc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Ester deprotection (Step C) The 2,6,-dicarboethoxy-3,7-diheptadecylthieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene (5.00 g, 7.39 mmol) product of Example 6, was dissolved in tetrahydrofuran (THF) (280 mL) then methanol (40 mL) was added. Lithium hydroxide (707 mg, 29.5 mmol) was dissolved in water (7 mL) and added to the stirred methanol and THF solution. A condenser was fitted and the reaction mixture was heated in an oil bath at 90° C. for 16 hr. The THF and methanol were removed under reduced pressure. 60 mL of methanol and 10 mL of conc. hydrochloric acid were added then stirred for 4 h. Next 50 mL of water was added and the solid was filtered off. The product was dried under vacuum to give the 3,7-didecanyl thieno[3,2-b]thieno[2′,3′:4,5]thieno[2,3-d]thiophene-2,6-dicarboxylic acid (4.50 g, 98% yield). 1H NMR (D8-THF)(of the di-lithium salt) δ 0.88 (6H, t, J=6.9 Hz), 1.20-1.47 (28H, m), 1.70-1.86 (4H, m), and 3.24 (4H, t, J=7.5 Hz).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](OC=C)(=[O:21])[CH3:20].C(Cl)(Cl)Cl>COC(C)(C)C>[C:1]([O:5][C@@H:6]1[CH2:10][C@H:9]([O:11][C:19](=[O:21])[CH3:20])[CH:8]=[CH:7]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=COC(C)=O
Reactant: CC(C)(C)O[C@H]1C=C[C@@H](O)C1
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1C=C[C@H](OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
Cis-4-tert-butyloxy-cyclopent-2-enol (485 mg, 3.1 mmol, prepared in example 9) is dissolved in tert-butyl methyl ether (8.6 mL, anhydrous). To the solution is added triethylamine (0.7 eq), pancreatin (3 wt eq, available from Sigma Chemical Company), and vinyl acetate (5 eq). The reaction is allowed to stir for 17 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum. The products are separated by chromatography on silica gel (10% to 20% ethyl acetate/hexane) to provide (-)-acetic acid cis-4-tert-butyloxy-cyclopent-2-enyl ester (B, 50% yield, 76% ee), [α]D =-10.9°, (c=0.98, chloroform), 1H NMR (CDCl3) δ5.94 (d, 1H, J=5.5 Hz), 5.89 (d, 1H, J=5.5 Hz), 5.46 (appt, 1H, J=5.5 Hz), 4.52 (appt, 1H, J=5.5 Hz), 2.8 (m, 1H), 2.0 (s, 3H), 1.6 (d appt, 1H, J=4.8, 14 Hz), 1.22 (s, 9H); 13C NMR (CDCl3) δ171.2, 138.6, 131.6, 77.4, 77.2, 41, 28.7, 28.6, 21.4; IR (neat) νmax 2976, 1738, 1364, 1242, 1196, 1067, 1020 cm-1 ; CIMS m/e (% relative intensity) 199 (M+H+, 4), 139 (M+H+ -AcOH, 70), 83 (100), and (-)-cis-4-tert-butyloxy-cyclopent-2-enol (A, 194 mg, 40% yield, >98% ee), [α]D 17.2°, (c=1.09, chloroform) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14][CH3:15])=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1)=O.[BH4-].[Na+]>C1COCC1.CO>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([O:14][CH3:15])[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][CH2:22][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCc3ccc(CC(=O)O)cc3)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product from step (vii) (9.7 g) and (4-formylphenyl)acetic acid (5.4 g) were dissolved in THF (100 ml) and stirred at rt for 4 h. Sodium borohydride (1.9 g) and 5 drops of methanol was added and stirred at a rt overnight. The mixture was quenched with water and concentrated under reduced pressure. Water was added and washed with diethyl ether. 0.1N—HCl was added to acidify the solution to pH 6. The suspension was filtered and the solid collected and dried under reduced pressure to give the subtitle compound. Yield 13 g.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[S:68][C:67]([C:69]#[N:70])=[CH:66][CH:65]=1>>[C:69]([C:67]1[S:68][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:70]
Reactant: N#Cc1ccc(N)s1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)s2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 26.6 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.46 g, 0.79 mmol), was reacted with diisopropylethylamine (0.51 g, 4 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 5-amino-thiophene-2-carbonitrile prepared in Example 186 (0.15 g, 1.2 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-thiophen-2-yl)-amide as a yellow solid (Yield 0.12 g, 26%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:35]([NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)NC1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C(=O)NC1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[CH2:10]([N:12](CC)CC)C.CN>ClCCl.C1COCC1>[CH3:10][NH:12][C:7]([C:5]1[N:6]=[C:2]([Cl:1])[S:3][CH:4]=1)=[O:8]
Reactant: O=C(Cl)c1csc(Cl)n1
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1csc(Cl)n1

Procedure:
To 445 mg (2.44 mmol) 2-chloro-thiazole-4-carbonyl chloride in 8.0 mL dichloromethane is added a mixture of 0.38 mL (2.69 mmol) triethylamine and 1.35 mL (2.69 mmol) 2 molars solution of methylamine in THF. The mixture is stirred over night, concentrated and the residue is treated with water and NaHCO3 solution. After extraction with ethylacetate the organic phases are combined, dried (Na2SO4) and concentrated to yield the desired product
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][CH2:12][CH:13]([OH:17])[C:14]([OH:16])=[O:15])[C:9]=2[N:10]=1.Cl.[CH2:20](O)[CH3:21]>>[CH2:20]([O:15][C:14](=[O:16])[CH:13]([OH:17])[CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:18])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2)[CH3:21]
Reactant: Nc1nc2c(ncn2CCC(O)C(=O)O)c(=O)[nH]1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)CCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(2-Amino-1,6-dihydro-6-oxopurin-9-yl)-2-hydroxybutyric acid (2.00 g, 7.9 mmole; prepared according to Example 3) was mixed with 500 ml of ethanol. The mixture was saturated with hydrogen chloride gas, first without cooling and then with cooling in ice-water. The total addition time was about 15 minutes. The mixture was then slowly warmed to room temperature and allowed to stand over night. After evaporation of the solvent, the residue was treated three times each with 25 ml of ethanol, the solvent being reevaporated after each treatment. The residue was then dissolved in 12 ml of water and the pH adjusted to 6-7 with saturated aqueous sodium bicarbonate. The precipitate was filtered off, washed with 2 ml of water and dried in vacuo to yield 1.60 g. Recrystallization from ethanol gave a pure product, m.p. 161°-3° C. (a sample for analysis had m.p. 162°-3° C.). Analyses--Found: C 46.96; H 5.35; N 24.77; O 22.60%. Calculated for C11H15N5O4 : C 46.97; H 5.38; N 24.90; O 22.75%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O-])([O-])=O.[K+].[K+].CI.O>CC(C)=O>[CH3:10][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(C=O)c1
Yield: 88 %

Procedure:
A solution of 3-hydroxybenzaldehyde (1.22 g, 10 mmol) in anhydrous acetone (50 mL) was treated with K2CO3 (2.76 g, 20 mmol) and MeI (0.9 mL, 15 mmol) at room temperature for 12 hours. The mixture was poured into water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the product was purified by flash column chromatography (0-15% EtOAc in hexanes, 1.2 g, 88% yield). 1H NMR (300 MHz, CDCl3) δ: 3.88 (s, 3H), 7.17-7.21 (m, 1H), 7.38-7.42 (m, 1H), 7.45-7.47 (m, 2H), 9.99 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=[CH2:22])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>O1CCCC1.O.CO>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=[CH2:22])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: C=CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)OCC)sc(N2CCOCC2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate (0.211 g, 0.453 mmol) in tetrahydrofuran (8.00 mL) was added 1.000 M of sodium hydroxide in water (10.0 mL) and methanol (4.00 mL). The resulting mixture was stirred at room temp over 3 hrs. The volatiles were removed under reduced pressure, and the resulting mixture was acidified with conc. HCl soln to pH˜2, and extracted with EtOAc (×3). The combined org layer was dried and concentrated to provide a purple syrup. Purification of the crude mixture on HPLC (AA, reverse phase) provided 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a white solid (63 mg, 31.8% yield). LCMS: (AA) ES− 391, 393, 395; 1H NMR (400 MHz, MeOD) δ 7.54-7.46 (d, J=1.6 Hz, 1H), 7.45-7.35 (d, J=8.4 Hz, 1H), 7.34-7.24 (dd, J=8.4, 1.6 Hz, 1H), 5.88-5.68 (m, 2H), 5.16-5.05 (dd, J=17.1, 1.7 Hz, 1H), 5.00-4.92 (m, 1H), 3.82-3.71 (t, J=4.8 Hz, 4H), 3.51-3.40 (t, J=4.8 Hz, 4H), 3.05-2.95 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=O.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>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:25])([F:24])[F:13]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Methyl 4-bromo-3-methylbenzoate (ABCR. 3 g; 13.10 mmol; 1 eq.), 2-(trifluoromethyl)phenylboronic acid (2.736 g; 14.41 mmol; 1.10 eq.), potassium carbonate (9.049 g; 65.48 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) were mixed in Toluene (15 mL) and water (15 mL) under N2 atmosphere. The reaction mixture was degassed with N2 for 10 min and was heated under reflux for 3 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (500 mL). The filtrate was concentrated under vacuum to afford brown oil. It was taken in EtOAc (500 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 (200 mL), water (200 mL) and brine (200 mL). It was dried over MgSO4, filtered off and concentrated under vacuum giving a brown oil (3.7 g, 96%). It was used in the next step without further purification. LC/MS (Method A): 294.5 (M+H)+. HPLC (Method A) Rt 5.34 min.