Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:2].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].N1CCCCC1>>[CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][N:5]1[C:16]([CH3:15])=[CH:17][C:18]([CH3:19])=[C:7]([C:8]#[N:9])[C:6]1=[O:10])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: CCCCC(CC)CNC(=O)CC#N
Solvent: C1CCNCC1
Product: CCCCC(CC)Cn1c(C)cc(C)c(C#N)c1=O
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of N-(2-ethylhexyl)cyanoacetamide (201.5 g., 1.0 mole), 2,4-pentanedione (100 g., 1.0 mole), piperidine (10 g.) and 2-B-ethanol 300 ml. is refluxed for 24 hours, cooled to room temperature and the solid precipitate is collected by filtration to give 155 g. (60% yield), mp. 84°-89° C. The solid when recrystallized from petroleum ether/benzene has a mp. 89°-90° C.
Reaction SMILES: C([CH:3]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)#N.C(=O)([O-])[O-:19].[K+].[K+]>O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)=[O:19])=[CH:5][CH:6]=1
Reactant: Cc1ccnc(C(C#N)c2ccc(F)cc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccnc(C(=O)c2ccc(F)cc2)c1
Reaction time: 8 h
Yield: 54.3 %

Procedure:
2-(α-cyano-4-fluorobenzyl)-4-methylpyridine (3.1 g) and potassium carbonate (2.9 g) were suspended in 20% hydrated dimethylsulfoxide (150 ml), and the suspension was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 2-(4-fluorobenzoyl)-4-methylpyridine (1.6 g) as brown crystals.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:37])C(=O)C1.O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[N:8]2[N:26]=[C:27]([CH3:29])[C:28]([Cl:37])=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nc(C)cc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n2nc(C)c(Cl)c2n1

Procedure:
5-n-Butyl-2-methyl-7-(3,4,5-trimethoxybenzoyl-amino) pyrazolo[1,5-a]pyrimidine (the compound of Example 53; 0.78 g) was dissolved in 10 ml of chloroform. After addition of 0.28 g of NCS, the mixture was refluxed with heating for 1 hour and allowed to cool. After addition of some water, the reaction mixture was extracted with chloroform. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2) and recrystallized from ethanol-n-hexane to provide 0.61 g of the object compound as colorless crystals. Table 3 shows the structure and melting point of the compound obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(O)[C:8]=2[CH:7]=1.C([Br:40])(=O)C>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([Br:40])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[CH:7]=1
Reactant: CC(=O)Br
Reactant: CC(C)CCCC(C)CCCC(C)CCOc1ccc2c(c1)C(O)(c1ccccc1)c1ccccc1-2
Solvent: ClC(Cl)Cl
Product: CC(C)CCCC(C)CCCC(C)CCOc1ccc2c(c1)C(Br)(c1ccccc1)c1ccccc1-2
Reaction time: 6 h
Yield: 62.2 %

Procedure:
The aforementioned 2-(3′,7′,11′-trimethyldodecyloxy)-9-phenylfluoren-9-ol (181 mg, 0.37 mmol) was dissolved in chloroform (2 ml), acetyl bromide (55 μl, 0.74 mmol) was added dropwise and the mixture was stirred for 6 hr. After completion of the reaction, the solvent was evaporated, and the residue was dissolved in heptane, and washed three times with acetonitrile. The solvent of the heptane layer was evaporated to give 2-(3′,7′,11′-trimethyldodecyloxy)-9-bromo-9-phenylfluorene (126 mg, 0.23 mmol, yield 62%).
Reaction SMILES: [I-:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]1[C:17]([CH3:18])=[CH:16][S:15][C:14]=1SC>CO>[I-:1].[CH3:18][C:17]1[N:13]2[C:14](=[NH+:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=32)[S:15][CH:16]=1
Reactant: CSc1scc(C)[n+]1-c1cc(C(F)(F)F)ccc1N
Agent: [I-]
Solvent: CO
Product: Cc1csc2[nH+]c3ccc(C(F)(F)F)cc3n12
Yield: 99.4 %

Procedure:
1.1 g (2.54 mmol) of 3-[2-amino-5-(trifluoromethyl)phenyl]-4-methyl-2-(methylsulfanyl)-1,3-thiazol-3-ium iodide (3a) were solubilised in MeOH (100 mL) and the solution refluxed for 7 days. Then MeOH was evaporated to yield 3-methyl-6-(trifluoromethyl)[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide (4a) (orange powder, 970 mg, 99%). Mp 122° C.; 1H NMR (300 MHz, CD3OD) δ=2.80 (3H, d, J=1.3, CH3), 6.88 (1H, q, J=1.3, H5), 7.65-7.71 (1H, m, Ar), 7.78-7.84 (1H, m, Ar), 8.17-8.22 (1H, m, Ar); 13C NMR (75 MHz, CD3OD) δ=14.12, 108.58, 110.25 (q, J=4), 119.02, 121.99 (q, J=4), 124.52 (q, J=33), 126.07 (q, J=271), 130.34, 132.58, 149.35, 161.08; HRMS m/z C11H8N2F3S [M−I]+ calcd: 257.0355, found: 257.0353.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[O:16]=[C:17]1[CH2:22][N:21]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19][N:18]1[C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(#N)C>[O:16]=[C:17]1[CH2:22][N:21]([C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])[CH2:20][CH2:19][N:18]1[C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: Nc1ccncn1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2ccncn2)cc1
Yield: 43.1 %

Procedure:
Synthesized according to general procedure 12, method B. The reaction was set up with 4-aminopyrimidine (0.26 g, 2.16 mmol), anhydrous acetonitrile (10 mL), DABCO (0.24 gm, 2.16 mmol) and 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride (0.80 g, 2.16 mmol). The dark oil was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by a second purification on silica gel using 80% methanol in dichloromethane to obtain the desired sulfonamide as a white solid (0.43 g, 0.93 mmol, 47% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=439.3; tR=2.3 min
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](Br)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])#[CH:32]>C(N(CC)CC)C.C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:20]=[C:21]([C:32]#[C:31][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(C#C[Si](C)(C)C)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 94.8 %

Procedure:
To a mixture of [4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (example 1-7) (51 mg, 0.10 mmol) and ethynyl-trimethyl-silane (20 mg, 0.20 mmol) in triethylamine (0.5 mL) and toluene (0.5 mL), was added copper(I) iodide (0.6 mg, 0.003 mmol) and bis(triphenylphosphine)palladium(II) chloride (2.4 mg, 0.003 mmol). The mixture was heated in a microwave oven at 80° C., for 20 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-trifluoromethyl-5-trimethylsilanylethynyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (50 mg, 94.8%) as a brown oil. MS calcd. for C23H28F3N3O4SSi 527, obsd (ESI+) [(M+H)+] 528.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([CH2:29][CH3:30])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.[OH-].[Na+].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(OCCCC)(=O)C>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([CH2:29][CH3:30])[C@@H:6]([OH:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOC(C)=O
Solvent: O
Product: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Temperature: 80 °C

Procedure:
A mixture of compound 6 (86 g, 205.4 mmol), water (688 mL) and 50% sodium hydroxide solution (56.4 mL) was reacted with sodium borohydride (7.77 g, 205.4 mmol) in a mixture of 50% wt. sodium hydroxide solution (1.5 mL) and water (20 mL) at 90° C. to 105° C. The reaction mixture was heated to reflux and stirred for at least 3 hours. For the workup, after the reaction was complete, the reaction mixture was cooled to approximately 80° C. and transferred to a cooled reactor. At 30° C. to 50° C., n-butyl acetate (860 mL) and citric acid (320.2 g, anhydrous) in water (491 mL) were added. The aqueous phase was separated and discarded after checking the pH-value to make sure that it was acidic. The organic phase was transferred and distilled. The residue is diluted with n-butyl acetate and was slowly cooled to 15° C. to 20° C. and the crude obeticholic acid was filtered using a centrifuge. The wet product was crystallized from n-butyl acetate. The product obeticholic acid was isolated and washed with n-butyl acetate (43 mL, 4 times) in an inert pressure filter. Drying was done in the pressure filter under vacuum at approximately 80° C. This led to 67.34 g (77.9%) of crystalline obeticholic acid. See example 3 for full details regarding the identification and characterization of crystalline obeticholic acid.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[OH-].[Li+].Cl>O1CCCC1.O>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC(F)F)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of C7 (17 g, 84 mmol) in tetrahydrofuran (100 mL) and water (50 mL) was cooled to 0° C. and treated with lithium hydroxide (6.0 g, 250 mmol). After the reaction mixture had stirred at room temperature for 2 hours, it was acidified to a pH of 3 with 1 M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried, filtered, and concentrated under reduced pressure to provide the product as a white solid. Yield: 13 g, 69 mmol, 82%. LCMS m/z 189.8 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=2.4 Hz, 1H), 8.29 (d, J=8.5 Hz, 1H), 7.73 (dd, J=8.6, 2.4 Hz, 1H), 6.68 (t, JHF=71.5 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:32]([N:35](CC2C=CC(OC)=CC=2OC)[C:36]2[S:40][N:39]=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:12][C:11]=1[C:26]1[CH:31]=[CH:30][N:29]=[N:28][CH:27]=1)#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([S:32]([NH:35][C:36]2[S:40][N:39]=[CH:38][N:37]=2)(=[O:33])=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)=[CH:12][C:11]=1[C:26]1[CH:31]=[CH:30][N:29]=[N:28][CH:27]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.2 %

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-{[3-pyridazin-4-yl-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 20, 386 mg, 0.52 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (13 mL) and stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using silica gel column chromatography (1% acetic acid in dichloromethane to 10% methanol and 1% acetic acid in dichloromethane gradient elution) followed by a second purification using silica gel column chromatography (0%-15% methanol in dichloromethane gradient elution) to afford the title compound (76 mg, 25%).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>>[OH:22][N:21]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21

Procedure:
A suspension of 4.0 g (15.86 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide and 3.86 g (55.49 mmol) of hydroxylamine hydrochloride in 100 mL of absolute alcohol was treated with 3.76 g (47.57 mmol) of pyridine. The mixture was heated at reflux for 1 hour and then the ethanol was removed by evaporation under reduced pressure. The residue was partitioned between 150 mL of water and 150 mL of dichloromethane. The organic layer was separated and washed with 50 mL of 1M aqueous HCl, a saturated solution of NaHCO3 and brine, then dried by sodium sulphate. Filtration and evaporation of the solvent under reduced pressure gave an off-white solid which was triturated with hot ethanol to give the desired compound as a white powder of m.p. 230.4° to 231.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([CH3:24])[CH:15]=3)[CH2:12][O:11]C(=O)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Li+]>O>[NH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[C:16]([CH3:24])[CH:15]=1)[CH2:12][OH:11]
Reactant: Cc1cc(C2(c3cccc(Br)c3)COC(=O)N2)ccc1OC(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(N)(CO)c2cccc(Br)c2)ccc1OC(F)F
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A solution of 4-(3-bromo-phenyl)-4-(4-difluoromethoxy-3-methyl-phenyl)-oxazolidin-2-one (intermediate XVII-2) (5.1 g, 1 eq) in a 9:1-mixture of ethanol and water (50 ml) was added lithium hydroxide (9.2 g, 30 eq). The reaction was stirred at reflux for 3 hours. Then the mixture was allowed to cool to room temperature and concentrated at reduced pressure. The residue was extracted with ethyl acetate (3×20 ml), the combined organic layers were collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel using a 5:1-mixture of cyclohexane and ethyl acetate as the eluent. There were obtained 4.8 g (93% of theory) of the (RS)-2-amino-2-(3-bromo-phenyl)-2-(4-difluoromethoxy-3-methyl-phenyl)-ethanol as a white solid.
Reaction SMILES: C([O:8][C:9](=[O:25])[C@@H:10]([NH:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>C1COCC1.[Pd]>[N:18]1([C:16]([NH:15][C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:25])=[O:8])=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Yield: 93.5 %

Procedure:
A solution of (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid benzyl ester (38.5 g, 111 mmol) in 600 mL of THF was hydrogenated at 50 psi over 20% Pd/C (2.00 g) for 17 minutes. The reaction mixture was filtered through celite and concentrated to dryness. The residue was heated in 50 mL of hexane. The resulting suspension was cooled, and the solid was collected by filtration and washed with hexane. The solid was dried at room temperature under vacuum to give (S)-2-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid as a white solid (26.6 g, 93%); mp 88-89° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:29])[CH3:9])=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1>>[CH3:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][NH:24][S:25]([CH3:28])(=[O:27])=[O:26])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:29])[CH3:9])=[CH:6][CH:7]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCNS(C)(=O)=O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCNS(C)(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)methanesulfonamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.12, m/z=494; 1H NMR (CDCl3) 1.48 (d, 3H), 2.10 (m, 2H), 2.20-2.41 (m, 2H), 2.43 (m, 1H), 2.71 (s, 3H), 2.73 (s, 3H), 3.11 (m, 2H), 5.52 (m, 1H), 7.13 (d, 2H), 7.25 (m, 3H), 7.34 (m, 2H), 7.62 (d, 2H), 7.91 (m, 1H), 8.08 (s, 1H), 8.56 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[C:5](F)=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:8]([CH3:9])=[N:14][NH:13][C:5]2=[CH:4][N:3]=1
Reactant: CC(=O)c1cc(Br)ncc1F
Reactant: NN
Solvent: OCCO
Solvent: O
Product: Cc1n[nH]c2cnc(Br)cc12
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
To a 250-mL round-bottomed flask equipped with a reflux condenser was added dry ethylene glycol (30 mL) and 325c (4.3 g, 20 mmol). Then hydrazine hydrate (5.0 mL, 4.8 g, 81.6 mmol) was added dropwise via a syringe. The mixture was heated at 165° C. for 3.5 h. The resulting orange-tan mixture was cooled to room temperature and the contents were poured onto a stirring mixture of 100 mL ice/water (1:1), whereupon precipitation occurred. After stirring for 10 min, the off-white precipitate was collected, which was dried in vacuo to afford 325d as an off-white solid (3.1 g, 74%). MS-ESI: [M+H]+ 211.9.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:26]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:32]=[CH:33][C:26]1=2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccc2sccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4sccc4c3)n2n1
Temperature: 110 °C
Yield: 36.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), benzo[b]thiophen-5-ylboronic acid (40 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (28 mg, 36%). 1HNMR (DMSO-d6) δ: 11.21 (s, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 7.99-8.04 (m, 3H), 7.93 (d, J=5.3 Hz, 1H), 7.67 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 5.20 (s, 1H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 443.2 (M+H)+.
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>C1(C)C=CC=CC=1>[C:5]([C:4](=[C:3]([S:9][CH3:10])[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:7]#[N:8])#[N:6]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1
Product: CSC(Nc1cccnc1)=C(C#N)C#N
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 11 g (64.6 mmol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 6 g (63.75 mmol) of 3-amino-pyridine and 50 ml of toluene is stirred at 60° C. for 18 hours. Filtration of the reaction mixture while still warm and washing of the filter residue with toluene yield 2-cyano-3-methylmercapto-3-(3-pyridylamino)-acrylonitrile; m.p. 180-181° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][O:5][CH2:4][CH2:3][O:6][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([Br:7])=[CH:9][CH:10]=2)=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: BrCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc(COCCOCc2ccc(Br)cc2)cc1
Yield: 94.2 %

Procedure:
To a solution of 603 mg (15.1 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (50 ml) was added 259 mg (4.17 mmol) of ethylene glycol in an atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. Then, 2.69 g (10.8 mmol) of 4-bromobenzyl bromide was added, and the mixture was reacted at room temperature for 20 hours. To the reaction mixture at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane yielded 1.57 g (3.93 mmol) of 1,6-bis(4-bromophenyl)-2,5-dioxahexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:18]([C:17]3[CH:20]=[CH:21][C:14]([O:13][CH2:12][CH2:11][OH:10])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1ccc(OCCO)cc1
Product: OCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-(2-hydroxyethoxy)benzaldehyde.