Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[S:9][C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][N:6]=1)(=O)C.C(O)(=O)C.Cl.[NH4+].[OH-]>O>[NH2:4][C:5]1[S:9][C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][N:6]=1
Reactant: CC(=O)Nc1nnc(C=Cc2ccc([N+](=O)[O-])cc2)s1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nnc(C=Cc2ccc([N+](=O)[O-])cc2)s1
Yield: 96.3 %

Procedure:
A mixture of 19.23 g (0.0664 m) of β-(5-acetamido-1,3,4-thiadiazol-2-yl)-p-nitrostyrene, 140 ml of acetic acid, and 140 ml of conc HCl was heated on a steam bath for 5 hr. The reaction mixture was cooled, poured into an equal amount of ice and water and neutralized with conc NH4OH. The product was collected on a Buchner funnel, washed with water, and air-dried to yield 15.84 g (0.0637 m, 96%) of the amine as a yellow-tan microcrystalline powder, MP. 289°-291° C. (dec).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][N:16]1[CH2:21][C@H:20]([CH3:22])[NH:19][C@@H:18]([CH3:23])[C:17]1=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:23][C@H:18]1[C:17](=[O:24])[N:16]([CH3:15])[CH2:21][C@H:20]([CH3:22])[N:19]1[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: C[C@@H]1N[C@@H](C)CN(C)C1=O
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C)C(=O)[C@@H]3C)nc12
Yield: 19.1 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (342 mg, 1.62 mmol), (3S,5S)-1,3,5-trimethylpiperazin-2-one (230 mg, 1.62 mmol) and potassium carbonate (670 mg, 4.85 mmol), in DMF (10 mL), was stirred at ambient temperature for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with 0.5 N HCl (10 mL), H2O (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solids were removed by filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 10% CH2Cl2 in EtOAc to 100% EtOAc) to give methyl 2-((2S,6S)-2,4,6-trimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (98 mg, 19%): 1H NMR consistent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].[O:17]1[CH:21]=[CH:20][C:19](O)=[N:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][O:15][C:19]3[CH:20]=[CH:21][O:17][N:18]=3)[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1OC(CO)CN1c1ccc(I)c(F)c1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1OC(COc2ccon2)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1.0 g, 2.97 mmol), isoxazol-3-ol (0.30 g, 3.56 mmol) and triphenylphosphine (1.02 g, 3.86 mmol) in THF (15 mL) was added diisopropyl azodicarboxylate (DIAD, 0.74 mL, 3.56 mmol) dropwise at 0° C. The reaction was warmed to room temperature and stirring was continued for 2 h. The solvent was evaporated and the crude was purified on silica gel, eluting with hexanes/EtOAc 2:1 to 3:2, to give 3-(3-fluoro-4-iodo-phenyl)-5-(isoxazol-3-yloxymethyl)-oxazolidin-2-one (1.01 g; 84% yield).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5][N:4]([CH3:16])[CH2:3]1.O1CCOCC1.[Cl:24]CCl>Cl>[F:1][C:2]1([F:17])[CH2:3][N:4]([CH3:16])[CH2:5][CH2:6][NH:7][CH2:8]1.[ClH:24]
Reactant: ClCCl
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCNCC(F)(F)C1
Temperature: 20 °C
Reaction time: 21 h

Procedure:
Combined a solution of tert-butyl 6,6-difluoro-4-methyl-1,4-diazepane-1-carboxylate (50 mg, 0.200 mmol) in dichloromethane (2 mL) and 4 M HCl in dioxane (0.4 mL, 1.6 mmol) and the solution stirred at 20° C. for 21 h. The reaction was then concentrated in vacuo to give the title compound as a hydrochloride acid salt which was used without further purification. MS: 151 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[N:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:58][N:59]([CH3:63])[CH2:60][CH2:61][NH2:62].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:58][N:59]([CH3:63])[CH2:60][CH2:61][NH:62][C:22]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([C:14]2[CH:13]=[N:12][C:11]3[N:10]([N:9]=[CH:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]=2)[N:21]=1)=[O:24]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(-c2cnc3c(-c4ccccc4)cnn3c2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1cccc(-c2cnc3c(-c4ccccc4)cnn3c2)n1

Procedure:
A solution of 6-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)pyridine-2-carboxylic acid (6-1, 100 mg, 0.32 mmol, 1 equiv), benzotriazole-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate (197 mg, 0.73 mmol, 1.2 equiv), N,N-dimethylethylenediamine (70 μL, 0.63 mmol, 2 equiv) and N,N-diisopropylethyl-amine (20 μL, 0.73 mmol, 2.3 equiv) in DMF (5 mL) was stirred at 23° C. for 3 hours. The solution was partitioned between EtOAc (3×100 mL) and water (120 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, then concentrated to afford N-[2-(dimethylamino)ethyl]-6-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)pyridine-2-carboxamide (6-2). 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1 H), 9.72 (s, 1 H), 9.42 (m, 1 H), 8.91 (s, 1 H), 8.47 (m, 1 H), 8.08 (m, 3 H), 7.48 (m, 2 H), 7.29 (m, 1 H), 3.73 (m, 2 H), 3.36 (m, 2 H), 2.89 (s, 3 H), 1.74 (s, 3 H).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([OH:5])=[O:4].[C:15](OCCCC)(=[O:17])[CH3:16]>>[C:15]([NH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([OH:5])=[O:4])(=[O:17])[CH3:16]
Reactant: CCCCCCCCCC(N)C(=O)O
Reactant: CCCCOC(C)=O
Product: CCCCCCCCCC(NC(C)=O)C(=O)O

Procedure:
20.1 parts of aminoundecanoic acid and 116.2 parts of butyl acetate were placed in a reactor equipped with a thermometer, a thermostat, a stirrer and a condenser, and allowed to react at 120° C. for 8 hours while azeotropically distilling off butanol. Further, 58.1 parts of butyl acetate was added, and allowed to react at 120° C. for 3 hours. Butanol and excess butyl acetate were distilled off under reduced pressure, thus giving an acetoamidoundecanoic acid. Then, 48.6 parts of the obtained acetoamidoundecanoic acid, 345 parts of dodecanoic diacid and 326.4 parts of acetic anhydride were placed in a reactor equipped with a thermometer, a thermostat, a stirrer and a condenser, and heated to 170° C. with stirring while distilling off acetic acid. After the distillation of acetic acid ceased, pressure was reduced to 30 mmHg at 170° C., followed by cooling the reaction mixture, thus giving an acid anhydride (a-4).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:33])[O:22][C@@H:23]1[CH2:28][C@H:27]([CH3:29])[CH2:26][CH2:25][C@H:24]1[CH:30]([CH3:32])[CH3:31].O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:21]([O:22][C@@H:23]2[CH2:28][C@H:27]([CH3:29])[CH2:26][CH2:25][C@H:24]2[CH:30]([CH3:32])[CH3:31])=[O:33])=[CH:7][CH:8]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)Cl
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.361 mmol, example 9 (step 3) and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl carbonochloridate (76.5 μL, 0.361 mmol) in DCM (1 mL) was stirred at RT for 16 h. Then, H2O (2 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as an off-white oil. MS (ESI, positive ion) m/z: 460 (M+H).
Reaction SMILES: O[CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH3:18])[C:6]1=O)[CH:3]=O.[NH2:20][NH2:21]>C1C=CC=CC=1>[CH3:18][CH:7]1[C:6]2[N:20]=[N:21][CH:3]=[CH:2][C:5]=2[CH2:10][CH2:9][N:8]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC1C(=O)C(C(O)C=O)CCN1C(=O)OC(C)(C)C
Reactant: NN
Solvent: c1ccccc1
Product: CC1c2nnccc2CCN1C(=O)OC(C)(C)C

Procedure:
To a solution of 70.0 mg (0.258 mmol) of tert-butyl 4-(1-hydroxyl-2-oxoethyl)-2-methyl-3-oxopiperidine-1-carboxylate (Step E) in 12 mL of benzene was added hydrazine. The reaction was heated to reflux for 3.5 h and concentrated to afford the title compound. LC/MS 194 (M+1-56).
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([N:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:12][CH2:11][O:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:24][CH:23]=2)=[O:9])=[CH:13][CH:14]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(C(=O)N2CC2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(C(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 80.7 %

Procedure:
1-(4-Isopropylbenzoyl)aziridine (1.89 g), 1.52 g of methyl p-hydroxybenzoate and 2.76 g of anhydrous potassium carbonate were added to 20 ml of N,N-dimethylformamide, the mixture was stirred at 59°-60° C. for 17 hours, the reaction solution was poured over ice water, the mixture was extracted with ethyl acetate, the extract was washed with 10% sodium hydroxide solution and then with water, dried with anhydrous magnesium sulfate, concentrated in vacuo, n-hexane was added to the residue, and the mixture was filtered to give 2.75 g (yield: 80.5%) of crystals, m.p. 89°-91° C.
Reaction SMILES: C(C1C=CC(S[CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH:21]=3)[NH:16][C:15]([CH3:32])([CH3:31])[CH:14]=2)=CC=1)(C)(C)C.BrCC1[C:44]2[C:39](=[CH:40][CH:41]=[C:42](C3C=CC=CC=3OC)[CH:43]=2)[NH:38]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC(C2C=CC=CC=2S)=CC=1)(C)(C)C>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:32])([CH3:31])[CH:14]=[C:13]2[CH2:12][NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1ccc(C(C)(C)C)cc1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: CC(C)(C)c1ccc(-c2ccccc2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(4-tert-Butylphenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 60 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 25 μL of 4-tert-butylphenylthiophenol reacted to give 9 mg of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:35])[NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Cl>C1COCC1.O.[OH-].[Li+]>[F:34][C:31]([F:32])([F:33])[C:28]1[N:27]=[CH:26][C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[O:35])=[CH:30][CH:29]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 60 mg (0.1 mmol), (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester in THF/H2O (10 mL; 4:1), 5 mL (4M) aqueous Lithium Hydroxide solution was added and the mixture stirred at 60° C. for 5 hours. Acidified with concentrated hydrochloric acid which precipitated the desired compound. Filtered and dried under vacuum to afford (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, which was subsequently dissolved in methanol (5 mL) one equivalent of potassium hydroxide and 2 mL of H2O were added and the resulting mixture was stirred at 40 C for 2 hours. Evaporated to dryness to afford (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid as the potassium salt: M+1=484.1. HRMS=484.1822. 1H NMR (400 MHz, MeOD) δ ppm 0.79 (d, J=7.33 Hz, 1H) 1.11 (td, J=12.44, 2.91 Hz, 3H) 1.43-1.55 (m, 2H) 1.67-1.78 (m, J=7.14, 7.14, 6.95, 6.57 Hz, 2H) 1.79-1.89 (m, 3H) 2.02 (d, J=7.33 Hz, 2H) 2.14 (t, J=7.33 Hz, 1H) 2.47 (s, 1H) 7.29 (d, J=8.34 Hz, 2H) 7.75 (d, J=8.59 Hz, 1H) 7.88-7.95 (m, 2H) 8.31 (dd, J=8.46, 2.40 Hz, 1H) 8.43 (dd, J=8.46, 2.15 Hz, 1H) 8.97 (d, J=2.27 Hz, 1H) 9.08 (d, J=1.52 Hz, 1H)
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][N:15]=2)=[N:6]1.[F:26][C:27]([F:37])([F:36])[CH2:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH:21][CH:32]3[CH2:31][CH2:30][N:29]([CH2:28][C:27]([F:37])([F:26])[F:36])[CH2:34][CH2:33]3)=[CH:16][N:15]=2)=[N:6]1
Reactant: O=C1CCN(CC(F)(F)F)CC1
Reactant: Nc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1NC1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
200 mg (0.596 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5-diamine (synthesis described in US2004/67937; Example V) were initially charged in methanol (16 ml) and admixed with 75 μl (1.312 mmol) of acetic acid, and then 237 mg (1.312 mmol) of 1-(2,2,2-trifluoroethyl)piperidin-4-one were added. After stirring at RT for 15 min, 104 mg (1.67 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 2.5 h. Subsequently, within 2 days, the above-stated amounts of reagents (1-(2,2,2-trifluoroethyl)piperidin-4-one, acetic acid, sodium cyanoborohydride) were added three times, in order to achieve substantially full conversion. Thereafter, saturated aqueous sodium hydrogencarbonate solution (5 ml) was added to the reaction mixture, which was stirred vigorously for 10 min. Subsequently, the reaction mixture was extracted with water and ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated and then purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 269 mg of the title compound were obtained (90% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]([OH:11])=[O:10])[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(C(=O)O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of diethyl 2-(4-fluorophenyl)malonate (2.98 g, 8.204 mmol, Intermediate 59, step a) and an aqueous 3 M NaOH solution (5 mL) were stirred in a 50° C. oil bath for 48 hours, cooled to RT, poured into ice water and acidified with 6N HCl. The aqueous mixture was extracted with EtOAc. The EtOAc extract was dried over Na2SO4, filtered, and evaporated in vacuo to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1CCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@@H]4CCCO4)c23)C1
Temperature: 160 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A mixture of (S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (195 mg, 0.594 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (357 mg, 1.78 mmol), and N-ethyl-N-isopropylpropan-2-amine (207 μL, 1.19 mmol) in n-BuOH (5 mL) were purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide tert-butyl (R)-1-(5-bromo-3-((S)-tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.295 mmol, 49.6% yield) as a solid. LCMS (APCI+) m/z 508.1, 510.1 (M+H)+; Retention time=3.85 minutes (Method 2).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])[O:11][N:10]=2)=[CH:5][CH:4]=1.P([O-])(O)(O)=[O:25].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O.C(#N)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]([OH:25])=[O:18])[O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)no2)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)no2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a mixture of 3-[3-(4-trifluoromethylphenyl)-5-isoxazolyl]benzaldehyde (0.539 g), sodium dihydrogen phosphate (0.204 g), 2-methyl-2-butene (1.80 ml), acetonitrile (40 ml) and water (10 ml) was added an aqueous solution (5 ml) of sodium chlorite (0.769 g), and the mixture was stirred at room temperature for 1 hr. To this mixture was added sodium sulfite (1.5 g), and the mixture was stirred for 10 min. and poured into 1 M hydrochloric acid. The crystals were collected by filtration and recrystallized from ethanol to give 3-[3-(4-trifluoromethylphenyl)-5-isoxazolyl]benzoic acid (0.451 g, yield 80%) as a colorless crystalline powder. melting point: 272–273° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH3:10][C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15]>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]2[CH3:10])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1cc(N)ccc1Br
Solvent: CC(=O)O
Product: Cc1cc(-n2c(C)ccc2C)ccc1Br
Yield: 82.5 %

Procedure:
Acetic acid (30 mL) solution of 9.30 g of 4-bromo-3-methylaniline and 6.85 g of 2,5-hexanedione was stirred at 80° C. for 5 hours. The reaction liquid was concentrated, aqueous saturated sodium hydrogencarbonate solution was added thereto, extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. This was filtered through silica gel column chromatography (ethyl acetate), the solvent was concentrated, hexane was added to it, and the formed solid was collected to obtain 10.90 g of the entitled compound as a white solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]1[N:12]=[C:11]2[C:13]([C:17]3[N:27]([S:28]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[C:20]4[N:21]=[CH:22][CH:23]=[C:24]([CH:25]=O)[C:19]=4[CH:18]=3)=[CH:14][N:15]([CH3:16])[C:10]2=[CH:9][C:8]=1[O:38][CH3:39].S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>ClCCl.CO>[CH:1]1([NH:4][CH2:25][C:24]2[CH:23]=[CH:22][N:21]=[C:20]3[N:27]([S:28]([C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)(=[O:30])=[O:29])[C:17]([C:13]4[C:11]5=[N:12][C:7]([O:6][CH3:5])=[C:8]([O:38][CH3:39])[CH:9]=[C:10]5[N:15]([CH3:16])[CH:14]=4)=[CH:18][C:19]=23)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reaction time: 48 h

Procedure:
To a solution of 0.141 cm3 of cyclopropylamine in 6 cm3 of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20° C., are added 0.2 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.4 g of sodium sulfate. Stirring is continued for 48 hours at room temperature. 6 cm3 of methanol and 0.031 g of sodium borohydride are added. The reaction medium is stirred at the same temperature for 24 hours. 100 cm3 of dichloromethane are added. The precipitate formed is filtered off and the filtrate is concentrated under reduced pressure and then purified by flash column chromatography (SiO2, dichloromethane/ethyl acetate 80/20 by volume as eluents) to give 0.110 g of cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-amine with the following characteristics:
Reaction SMILES: [CH2:1]([C:13]1[C:21]2[S:22][CH:23]=[CH:24][C:20]=2[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:15]2[S:16][CH:17]=[CH:18][C:14]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.[CH3:42][Sn:43](Cl)([CH3:45])[CH3:44].O>O1CCCC1>[CH2:1]([C:13]1[C:21]2[S:22][C:23]([Sn:43]([CH3:45])([CH3:44])[CH3:42])=[CH:24][C:20]=2[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:15]2[S:16][C:17]([Sn:43]([CH3:45])([CH3:44])[CH3:42])=[CH:18][C:14]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1c2ccsc2c(CCCCCCCCCCCC)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1c2cc([Sn](C)(C)C)sc2c(CCCCCCCCCCCC)c2cc([Sn](C)(C)C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Preparation of 4,8-didodecyl-2,6-Bis-trimethylstannylbenzo[1, 2-1):4,5-b′]dithiophene. To a solution of 4,8-didodecylbenzo[1,2-b:4,5-b′]dithiophene (553 mg, 1.05 mmol) in dry tetrahydrofuran (16 mL) was added n-butyllithium (2.5 M in hexane, 0.92 mL, 2.31 mmol) at −78° C. After 1 hour, trimethyltin chloride (488 mg, 2.45 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, poured into water and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained which is recrystallized from EtOH to give a white solid (524 mg, yield 58%). 1H NMR (CDCl3, 500 MHz) δ=7.51 (s, 2H), 3.22 (t, J=8.0 Hz, 4H), 1.76-1.91 (m, 4H), 1.36-1.42 (m, 4H), 1.22-1.42 (bs, 32H), 0.91 (t, J=7.0 Hz, 6H), 0.47 (s, 18 H). See also, Chem. Mater. 2006, 18, 3237.