Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.OC(C(F)(F)F)=O.[N:21]1([C@@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)[CH:25]=[N:24][CH:23]=[N:22]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:32][C@H:29]2[CH2:28][CH2:27][C@@H:26]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[CH2:31][CH2:30]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N[C@H]1CC[C@@H](n2cncn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@@H](n2cncn2)CC1
Temperature: 90 °C
Yield: 20.2 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.10 g, 0.46 mmol), cis-4-(1H-1,2,4-triazol-1-yl)cyclohexanamine TFA salt (0.10 g, 0.60 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) in isopropyl alcohol (1.0 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 10% EtOAc in dichloromethane) to give the desired product (32 mg, 20%). LCMS calculated for C15H17N6O2S (M+H)+: m/z=345.1. Found: 345.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([OH:32])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[C:24]([O:32][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(O)c2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 66.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.00 g, 5.74 mmol) and 3-(1-cyano-1-methylethyl)-N-[3-hydroxy-4-(trifluoromethyl)phenyl]benzamide (955 mg, 6.02 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.18 g, 8.61 mmol), and the mixture was stirred at 80° C. for 20 hr. After the reaction mixture was cooled to room temperature, water (150 mL) was added, and the mixture was twice extracted with ethyl acetate/hexane (75 mL/75 mL). The combined organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70). The obtained solution was concentrated under reduced pressure to give the title compound (1.79 g, 66%) as a yellow amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[H-].[Na+].Br[C:29]1[S:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1>CN(C=O)C>[S:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: Brc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc4ccccc4s3)nc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
To a solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 21.2 mg, 0.063 mmol) in DMF (626 μL) was added sodium hydride (10.02 mg, 0.251 mmol) in one portion. After 20 min, 2-bromo-1,3-benzothiazole (53.6 mg, 0.251 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organics were washed with 10% LiCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography using an Isco 4 g column eluting with 0-5% MeOH/CH2Cl2 to yield 4-(benzo[d]thiazol-2-ylamino)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (6.8 mg, 21.87% yield) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2=[C:6]([CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=3)[C:7]3[C:12]([N:4]2[CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH2:26][OH:27]>CO>[OH:27][NH:26][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]3[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]=23)=[CH:23][CH:22]=1
Reactant: NO
Reactant: COC(=O)c1ccc(Cc2c3n(c4ccccc24)CN(C)CC3)cc1
Solvent: CO
Product: CN1CCc2c(Cc3ccc(C(=O)NO)cc3)c3ccccc3n2C1

Procedure:
A solution of methyl 4-((2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indol-5-yl)methyl)benzoate (0.07 g) and 1 mL of 50% aqueous solution of NH2OH in 3 mL of MeOH was stirred at r.t. for 12 h, and the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography eluted with up to 10% MeOH/CH2Cl2 to give 0.02 g of the title product as white solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35].Br[CH2:37][CH2:38][CH2:39][Cl:40]>>[ClH:40].[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:37][CH2:38][CH2:39][N:30]3[CH2:34][CH2:33][CH2:32][C:31]3=[O:35])[CH2:24][CH2:23]2)[C:8](=[O:21])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: ClCCCBr
Reactant: CC(C)COc1ccc(CC(=O)N(Cc2ccc(F)cc2)C2CCNCC2)cc1
Product: CC(C)COc1ccc(CC(=O)N(Cc2ccc(F)cc2)C2CCN(CCCN3CCCC3=O)CC2)cc1
Product: Cl
Yield: 11 %

Procedure:
The desired compound was synthesized from N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl) N-piperidin-4-yl-acetamide 103NLS56 (107 mg, 0.27 mmol), 2-pyrrolidone and 1-bromo-3-chloropropane using the same method as for synthesis of 98AF73-64. Purification of the product by silica gel column chromatography, eluting with a stepwise gradient of 4-8% methanol in dichloromethane, afforded the title compound (15 mg, 11%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][C@H:18]([NH:17][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=2)[CH2:27][CH2:26]3)[CH2:29][CH2:30]1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2cccc(Oc4ccccc4)c2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Phenoxybenzoic acid (1.0 g, 4.7 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (99 mg, 0.42 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (99 mg, 0.41 mmol) and triethylamine (83 μL, 0.42 mmol) in methylene chloride (20 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 120 mg (68%) of the title compound as an oil. The oil crystallized from diethyl ether/hexane: mp 136-137° C.; [α]21D −9.0° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 441 (31, M+).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][C:44]([OH:47])([CH3:45])[CH3:46])[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(CC(C)(C)O)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(2-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75. Mass spectrum (ESI+): m/z=519 [m+H]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH2:6][NH2:7].[OH-:11].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:13]([NH:2][C@@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH2:6][NH:7][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCC[C@@H](N)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1

Procedure:
A solution of D-ornithine monohydrochloride in 60 ml. of 2N sodium hydroxide was cooled to 5°C. Carbobenzoxy chloride (20.4 g.) and 2N sodium hydroxide (64 ml.) were added in four equal portions over 1.0 hour with stirring. The mixture was stirred for an additional 0.5 hour in the cold, then extracted with diethyl ether. The aqueous portion was chilled and acidified (25 ml. 6N hydrochloric acid) and the resulting oil was extracted into ether containing some ethyl acetate. The organic phase was extracted with water, then saturated salt solution and dried (MgSO4). Evaporation of the solvent gave an oil which crystallized from ether to afford 18.8 gms. of product, m.p. 110.5°-113°C.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li+].CCC[CH2-].C(#N)C.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>C1COCC1.O>[NH2:23]/[C:22](/[C:21]1[CH:24]=[CH:25][C:18]([C:17]([F:26])([F:27])[F:16])=[CH:19][CH:20]=1)=[CH:2]\[C:1]#[N:4]
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)NC(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: N#C/C=C(\N)c1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
28.1 g (278 mmol) of diisopropylamine are introduced into 450 ml of THF at −70° C. in a three-neck flask with mechanical stirrer under argon. 148 ml of N-butyllithium solution (1.6 M in hexane, 237 mmol) are added dropwise at such a rate that the temperature does not rise above −60° C. The mixture is stirred for 10 min and then a solution of 12.9 ml (245 mmol) of acetonitrile in 100 ml of THF is slowly added dropwise, and the suspension is stirred for 30 min. Then a solution of 28 g (164 mmol) of 4-(trifluoromethyl)benzonitrile in 100 ml of THF is added dropwise, and the mixture is stirred at −70° C. for 20 min. It is allowed to reach RT slowly and is stirred at RT for a further 16 h. 150 ml of water are added, most of the THF is distilled off, and water and dichloromethane are added. The organic phase is washed with saturated aqueous sodium chloride solution. Removal of the solvent results in dark crystals which are purified by stirring with diisopropyl ether (40 ml once, 20 ml twice). The crystals are filtered off, washed with petroleum ether and dried. 27 g (78% of theory) of the product are obtained as a solid.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[C:12]([O:16][C:17]([N:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:21]=[C:20]1[NH2:31])=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCCl.ClCCl>[C:12]([O:16][C:17]([N:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:21]=[C:20]1[NH2:31])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(CCCC(=O)O)nc1N
Temperature: 60 °C

Procedure:
General Aminolysis Procedure: To a stirring 0° C. solution of amine (0.704 mmol) in anhydrous 1,2-dichloroethane (1 mL) was added drop-wise a 2M solution of AlMe3 in PhCH3 (0.351 mL, 0.704 mmol). The solution was stirred for 10 min before the addition of 2-amino-4-(3-methoxycarbonyl-propyl)-imidazole-1-carboxylic acid tert-butyl ester 18 (100 mg, 0.352 mmol) in several portions. Once dissolution was complete, the reaction was warmed to 60° C. and stirred until completion as evident by TLC analysis. The reaction was then cooled back down to 0° C. before being diluted with dichloromethane (5 mL) and quenched with water (1 mL). The resulting viscous solution was warmed to ambient temperature and Celite® diatomite was added. After stirring for 5 min, the mixture was filtered and the filtrate washed with brine (2×3 mL), dried (Na2SO4), and evaporated to dryness. The crude product was purified via flash column chromatography (2-10% MeOH/CH2Cl2) to afford pure product.
Reaction SMILES: C(Cl)[Cl:2].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(Cl)(Cl)(=O)=O>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:21])[CH:19]([Cl:2])[CH3:20])=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: ClCCl
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: CC(Cl)C(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a methylene chloride solution (20 mL) of 4.80 g (20 mmol) of p-(benzyloxy)propiophenone, 2.97 g (1.1 equivalents) of sulfuryl chloride was added at 15° C., followed by 16 hours of stirring. After 20 mL of water was added, methylene chloride was distilled off under a reduced pressure, and extraction was conducted by adding 40 mL of ethyl acetate. The organic layer was washed with 20 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvent. A colorless, oily substance (6.299 g) was thereby obtained. The oily substance was crystallized from 0.5 mL of ethyl acetate and 20 mL of hexane to obtain white crystals of 1-[4-(benzyloxy)phenyl]-2-chloro-1-propanone (4.3787 g, isolation yield: 75%).
Reaction SMILES: [CH2:1]([C:9]1[S:13][C:12]2[S:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([CH:24]([CH2:27]O)[CH2:25][OH:26])[CH2:20][CH2:21][CH2:22][CH3:23].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C:9]1[S:13][C:12]2[S:14][C:15]([C@H:17]3[O:26][CH2:25][C@H:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:27][O:18]3)=[CH:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cc2cc(C=O)sc2s1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCc1cc2cc([C@H]3OC[C@H](CCCCC)CO3)sc2s1

Procedure:
20.4 g of 5-n-octylthieno[2,3-b]thiophene-2-carbaldehyde (obtainable from 2-n-octylthieno[2,3-b]thiophene by Vilsmeyer formylation with phosphorus oxychloride/dimethylformamide) and 9.5 g of 2-n-pentylpropane-1,3-diol are dissolved in 150 ml of toluene, a pinch of toluenesulfonic acid is added, and the mixture is heated under a water separator until water is no longer separated off. The acid is washed out with sodium bicarbonate solution, the organic phase is dried over sodium sulfate, and the toluene is distilled off. The pure trans-2-(5-n-octylthieno[2,3-b]thien-2-yl)-5-n-pentyl-1,3-dioxane is obtained by repeated recrystallization from ethanol (17.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(OC([N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:33]=2[C:34](O)=[O:35])[CH2:27][CH2:26]1)=O)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([O-:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[C:41]([C:39]1[CH:38]=[CH:37][C:33]([C:34]([NH:1][C:2]2[C:3]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=3)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:35])=[C:32]([O:31][CH:28]2[CH2:27][CH2:26][NH:25][CH2:30][CH2:29]2)[CH:40]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)O)CC1
Reactant: O=C([O-])C(F)(F)F
Product: CC(C)(C)c1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Product: O=C(O)C(F)(F)F
Yield: 30 %

Procedure:
Using methods substantially equivalent to those described in Example 1-I, 3-amino-N-(5-chloropyridin-2-yl)-pyridine-2-carboxamide (626 mg, 2.52 mmol) and 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-tert-butylbenzoic acid (500 mg, 1.47 mmol) yielded, after deprotection of the coupled product using methods substantially equivalent to those described in Example 1-J, 470 mg (30%) of the title compound as a trifluoroacetate salt.
Reaction SMILES: [Li+].CON(C)[C:5]([CH2:7][C@H:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:6].[Cl:32][C:33]1[CH:38]=[C:37](I)[CH:36]=[CH:35][N:34]=1.C(N(CC)C(C)C)(C)C>>[Cl:32][C:33]1[CH:38]=[C:37]([C:5](=[O:6])[CH2:7][C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:36]=[CH:35][N:34]=1
Reactant: Clc1cc(I)ccn1
Reactant: CON(C)C(=O)C[C@H](c1ccc(-c2ccc(C(=O)[O-])cc2)cc1)c1ccccc1C
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1[C@H](CC(=O)c1ccnc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 74, step 5, from 4′-[(R)-2-(methoxy-methyl-carbamoyl)-1-o-tolyl-ethyl]-biphenyl-4-carboxylic acid lithium salt, 2-chloro-4-iodopyridine and N,N-diisopropyl-ethylamine was prepared the title compound as a brown foam, MS (ESI−): m/z=454.1 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][OH:12].O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)cc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc2ccccc21
Yield: 46.6 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 4.30 g of 1-methylindol-2-ylmethanol (prepared as described in Preparation 23), 10.3 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 6.65 ml of tributylphosphine, 6.73 g of 1,1'-(azodicarbonyl)dipiperidine and 120 ml of benzene were used, to give 6.28 g of the title compound, melting at 134.3-136.0° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[CH3:20][S:21]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[N:7]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(CO)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(COS(C)(=O)=O)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
(6-Methyl-5-nitropyridin-2-yl)methanol (12 g, 71 mmol), and triethylamine (9.4 g, 93 mmol) in THF (300 mL) was chilled in an ice bath to 10° C. and methanesulfonyl chloride (9.0 g, 79 mmol) was added dropwise and the solution was stirred for one hour, then filtered to remove triethylamine HCl, and the solvent was removed under reduced pressure on the rotovap (with the bath temperature at 35° C.) and (6-methyl-5-nitropyridin-2-yl)methyl methanesulfonate (17 g, 97%), a brown oil which was directly used as such. 1HNMR (CDCl3, 400 MHz) δ 2.87 (s, 3H), 3.16 (s, 3H), 5.83 (s, 2H), 7.55 (d, J=8.34, 1H), 8.38 (d, J=8.34, 1H); Exact mass calculated for C8H10N2O5: 246.03. found: 247.10 MS m/z (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1.[ClH:29].C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(O)C>[ClH:29].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:34])[NH2:28])[CH:22]=1
Reactant: Cn1c(COc2cccc(C#N)c2)nc2cc(S(=O)(=O)N3CCCC3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(COc2cccc(C(=N)N)c2)nc2cc(S(=O)(=O)N3CCCC3)ccc21
Yield: 71 %

Procedure:
Prepared analogously to Example 32 from 1-methyl-2-[(3-cyanophenyl)oxymethyl]benzimidazol-5-yl-sulfonic acid-pyrrolidide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 71% of theory, C20H23N5O3S (413.5); EKA mass spectrum: (M+H)+=414.