Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[Cl:8].CS(O[CH2:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[CH2:16][CH2:17][CH2:18][CH3:19])(=O)=O.Cl>CCOCC.O.CN(C)C=O.CO>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][N:4]1[C:3]([Cl:2])=[C:7]([Cl:8])[N:6]=[CH:5]1
Reactant: CCCCC(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Reactant: Clc1nc[nH]c1Cl
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCC(Cn1cnc(Cl)c1Cl)c1ccc(Cl)cc1Cl
Yield: 46.8 %

Procedure:
To 100 ml of methanol is added 1.7 g (0.0735 moles) of sodium. When the sodium dissolves, 10 g (0.0735 moles) of 4,5-dichlorimidazole is added. The mixture is stirred until a solution forms, and then the methanol is stripped off. The wet residue is then added to 50 ml of dimethyl formamide and the solution heated up to 125° to remove the remaining methanol and water. The solution is cooled to less than 100° and 2.5 g (0.0735 moles) of 2-(2,4-dichlorophenyl)hexyl methane sulfonate is added. The reaction is heated up to 130° for two hours and then cooled. The reaction is poured into water and the organic material extracted three times with 200 ml of benzene. The combined extracts are washed twice with 50 ml of water, dried over anhydrous magnesium sulfate and concentrated to obtain 15.8 g of the crude product. The residue is dissolved in ether, and treated with dry hydrogen chloride gas. The ether solution is decanted from the oil which forms and the oil is triturated twice with 150 ml of ether. The oil is then treated with 10% sodium hydroxide, and the product extracted out twice with 200 ml of ether. The ether solution is dried and concentrated to give 12.6 g (47%) of the oil product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([O:21][C:19](=[O:26])[NH:20][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(N)=O
Reactant: COc1cccc(-c2nc3cc(Br)ccn3n2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(-c2nc3cc(NC(=O)OC(C)(C)C)ccn3n2)c1
Temperature: 100 °C
Yield: 50.2 %

Procedure:
A solution of 7-bromo-2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (5.0 g, 16.4 mmol), tert-butyl carbamate (2.88 g, 24.7 mmol) and cesium carbonate (10.6 g, 32.9 mmol) in dioxane (85 ml) was degassed well with argon for 20 min at 25° C. To this solution was then added tris(dibenzylideneacetone)dipalladium(0) (3.0 g, 3.28 mmol) and xantphos (3.8 g, 6.57 mmol), and the resulting mixture was degassed again with argon for another 20 min. The reaction mixture was heated at 100° C. under argon atmosphere for 16 h. The reaction mixture was diluted with EtOAc (500 ml). The organic layer was washed successively with water (2×250 ml) and brine (100 ml), dried over anhydrous Na2SO4, filtered, and evaporated in vacuum. The crude material thus obtained was purified by column chromatography over silica gel (20-40% EtOAc/hexane) to afford [2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (2.8 g, 51%) as yellow solid. LC-MS: m/z=341 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:16]=1)[C:10]1[CH:9]=[C:8]3[C:33]([CH3:41])([CH3:40])[C:34]4[C:39]([C:7]3=[CH:6][C:5]2=1)=[CH:38][CH:37]=[CH:36][CH:35]=4.[C:42]1([C:48]2[CH:49]=[CH:50][C:51]3[NH:52][C:53]4[C:58]([C:59]=3[CH:60]=2)=[CH:57][C:56]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:55][CH:54]=4)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:42]1([C:48]2[CH:49]=[CH:50][C:51]3[N:52]([C:2]4[CH:3]=[C:4]5[C:12](=[CH:13][CH:14]=4)[N:11]([C:15]4[N:20]=[C:19]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)[N:18]=[C:17]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[N:16]=4)[C:10]4[CH:9]=[C:8]6[C:33]([CH3:40])([CH3:41])[C:34]7[C:39]([C:7]6=[CH:6][C:5]5=4)=[CH:38][CH:37]=[CH:36][CH:35]=7)[C:53]4[C:58]([C:59]=3[CH:60]=2)=[CH:57][C:56]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)=[CH:55][CH:54]=4)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Reactant: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: CC1(C)c2ccccc2-c2cc3c4cc(-n5c6ccc(-c7ccccc7)cc6c6cc(-c7ccccc7)ccc65)ccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21

Procedure:
20 g (33.7 mmol) of 7-bromo-10-(4,6-diphenyl-1,3,5-triazin-2-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene, 12 g (37.6 mmol) of 3,6-diphenyl-9H-carbazole and 23.34 g of Rb2CO3 are suspended in 200 ml of p-xylene. 0.76 g (3.4 mmol) of Pd(OAc)2 and 10.1 ml of a 1 M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 20 g (24 mmol), 72% of theory.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[CH:32][CH:31]=3)[CH:7]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.52) (0.11 g, 0.27 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.079 g, 0.36 mmol) according to the general procedure VI. Obtained as a light brown solid (0.021 g, 18%). MS (ISP) 422.1 [(M+H)+]; mp 188° C.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][C:30]([CH3:36])([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]4)=[N:25][CH:26]=3)[C:18]([F:20])=[CH:19][C:14]2=[N:13][C:12]=1[CH3:37]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.CCOC(C)=O>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[CH2:32][CH2:31][C:30]([CH3:36])([C:33]([O:35][CH2:9][CH2:4][CH2:5][CH3:6])=[O:34])[CH2:29][CH2:28]4)=[N:23][CH:22]=3)[C:18]([F:20])=[CH:19][C:14]2=[N:13][C:12]=1[CH3:37]
Reactant: Cc1nc2cc(F)c(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C1(C)CCN(c2ncc(-c3cn4c(Cc5ccccc5OC(F)F)c(C)nc4cc3F)cn2)CC1
Temperature: 180 °C
Yield: 81.4 %

Procedure:
A suspension of the sodium salt of Example 46 (207 mg, 0.38 mmol) and tetra-n-butylammonium chloride (42 mg, 1.5 mmol) in DMSO (2.5 mL) was heated under microwave irradiation, in a sealed tube, to 180° C. for 10 minutes. The reaction mixture was diluted with EtOAc (30 mL), and washed with HCl (1M, 20 mL), water (2×20 mL) and brine (20 mL), then the organic layers were dried over MgSO4 and the solvent was removed. The resulting crude yellow gum (270 mg) was purified by uv-directed preparative HPLC (pH 10 method eluting with 50-65% solvent B) to give the title compound (90 mg, 41%) as a colourless gum. δH (400 MHz, CD3OD) 8.39 (s 2H), 8.10 (d, 1H, J 7.3 Hz), 7.32-7.26 (m 2H), 7.21 (m, 1H), 7.16 (t, 1H, J 7.7 Hz), 7.10-7.08 (m, 1H), 6.92 (t, 1H, J 74 Hz), 4.42 (t, 2H, J 4.0 Hz), 4.38 (s, 2H), 4.18 (t, 2H, J 6.4 Hz), 3.40-3.37 (m, 2H), 2.42 (s, 3H), 2.17 (d, 2H, J 13.6 Hz), 1.69 (m, 2H), 1.51-1.42 (m, 4H), 1.26 (s, 3H), 0.99 (t, 3H, J 7.3 Hz). HPLC-MS (pH 10): MH+ m/z 582.8, RT 3.04 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:16])[CH:13]=[N+]=[N-])[CH:6]=[CH:5]2.[BrH:17].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:17][CH2:13][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)=[O:16]
Reactant: [N-]=[N+]=CC(=O)c1ccc2cc(Br)ccc2c1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reaction time: 3 h

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-diazoethanone (34.7 g) were dissolved in ethyl acetate (500 mL), and hydrobromic acid solution (21.1 mL, 5.7 M in acetic acid) was added at 0° C. Reaction mixture was stirred 3 hours, NaHCO3 solution (200 mL) was added, and mixture was stirred 10 minutes. Ethyl acetate solution was extracted twice with NaHCO3 solution (50 mL), once with brine (50 mL), and evaporated under vacuum, giving 2-bromo-1-(6-bromonaphthalen-2-yl)-ethanone (33.0 g, crude) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([N:13]3C(=O)C4C(=CC=CC=4)C3=O)=[N:9]2)[CH2:4][O:3]1.CN.CCCCCCC>C(OC)(C)(C)C.C(O)C>[CH3:1][C:2]1([CH3:24])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N3C(=O)c4ccccc4C3=O)n2)O1
Agent: CN
Solvent: CCCCCCC
Solvent: COC(C)(C)C
Solvent: CCO
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A suspension of 2-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-isoindole-1,3-dione (5.00 g, 15.3 mmol) in methyl t-butyl ether (50 mL) and ethanol (30 mL) was cooled with an ice water bath, and 33 wt. % methylamine in ethanol (20.0 mL, 161 mmol) was added. After 30 min, the mixture was warmed to room temperature and stirred for 2 h. Heptane (50 mL) was added and the mixture was cooled (−20° C.) for 30 min. The resulting solids were removed by filtration and rinsed with heptane. The filtrate was partially concentrated to a volume of ˜50 mL. The resulting solids were removed by filtration and rinsed with methyl t-butyl ether and heptane. After concentration of the filtrate to dryness, a yellow oil remained, which was then dissolved in methyl t-butyl ether (15 mL) and cooled (−20° C.) for 30 min. Addition of seed crystals and scratching with a spatula initiated crystallization of the product. Heptane (30 mL) was added and the suspension was cooled (−20° C.) for 30 min. Subsequent filtration, washing with heptane, and suction drying afforded 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (2.85 g, 94.6%) as a white solid: LR-ES-MS m/z calculated for C9H15N3O2 [M]+ 197, observed [M+H]+ 198.
Reaction SMILES: [CH3:1][O-:2].C[O-].[CH2:5]([Sn+2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]>C(O)CC>[O-:2][CH2:5][CH2:6][CH3:7].[O-:2][CH2:1][CH2:5][CH3:6].[CH2:5]([Sn+2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8]
Reactant: C[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCCO
Product: CCC[O-]
Temperature: 100 °C

Procedure:
A carbon dioxide complex-containing mixture was produced using an apparatus as shown in FIG. 5. Approximately 1000 g of dibutyltin dimethoxide (made by Aldrich, USA) and approximately 7500 g of 1-propanol (made by Wako Pure Chemical Industries, Ltd., dehydrated grade) were fed via a transfer line 4 into a tank reactor 220 equipped with a stirrer, and the liquid mixture was heated to approximately 100° C., so as to produce dibutyltin dipropoxide. Methanol-containing 1-propanol produced from the reaction was recovered from a transfer line 6, and a dibutyltin dipropoxide-containing alkyltin alkoxide composition was transferred via a transfer line 5 into a thin film evaporator 130, where 1-propanol was evaporated off, and recovered via a condenser 132 and a transfer line 8. The alkyltin alkoxide composition was obtained from a lower portion of the thin film evaporator 130, this composition containing approximately 92 wt % of dibutyltin dipropoxide and approximately 7 wt % of 1,1,3,3-tetrabutyl-1,3-di(propyloxy)-distannoxane. The composition was cooled to approximately 95° C. using a cooler 131, and transferred into an upper portion of a carbon dioxide complex production apparatus 140 at a flow rate of approximately 1175 g/hr via a transfer line 7. A column reactor 240 of inside diameter 53.5 mm and effective length 2680 mm (packed length approximately 2000 mm) packed with a Dixon packing (made by Tokyo Tokushu Kanaami, Japan, size 6 mm) and equipped with a cooling jacket as shown in FIG. 7 was used as the carbon dioxide complex production apparatus 140. Gaseous carbon dioxide (made by Showa Tansan Co., Ltd., Japan, purity 99.99%, water content not more than 40 ppm) was supplied at normal pressure at approximately 200 g/hr via a transfer line 9 into a lower portion of the column reactor 240. The reaction temperature in the column reactor 240 was adjusted to approximately 100° C., and a carbon dioxide complex-containing mixture was produced. The mixture was a liquid, and was transferred out at normal pressure at a temperature of 100° C. via a transfer line 10, it being possible to carry out the transfer via the transfer line 10 without problems such as blockage of the line occurring. The mixture was sampled, and subjected to elemental analysis, whereupon the molar ratio between tin atoms, carbon dioxide, and OR groups in the mixture (Z:(CO2)x:(OR)y) was found to be such that x=0.25 and y=1.88.
Reaction SMILES: [CH2:1]([Si:9]([CH2:16][CH:17]=[CH2:18])([CH2:13][CH:14]=[CH2:15])[CH2:10][CH:11]=[CH2:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:19][SiH:20]([Cl:22])[Cl:21]>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pt+2]>[CH2:1]([Si:9]([CH2:16][CH2:17][CH2:18][Si:20]([Cl:22])([Cl:21])[Cl:19])([CH2:10][CH2:11][CH2:12][Si:20]([Cl:22])([Cl:21])[Cl:19])[CH2:13][CH2:14][CH2:15][Si:20]([Cl:22])([Cl:21])[Cl:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CC[Si](CC=C)(CC=C)CCCCCCCC
Reactant: Cl[SiH](Cl)Cl
Agent: [Pt+2]
Agent: CC(=O)/C=C(/C)[O-]
Product: CCCCCCCC[Si](CCC[Si](Cl)(Cl)Cl)(CCC[Si](Cl)(Cl)Cl)CCC[Si](Cl)(Cl)Cl
Temperature: 40 °C
Reaction time: 288 h
Yield: 74.1 %

Procedure:
In an inert atmosphere enclosure, into a 200 Ml glass ampoule equipped with a Teflon/glass valve and magnetic stirring bar were added platinum acetylacetonate (0.04 g, 0.1 mmol) and n-octyltriallylsilane (20.0 g, 75.6 mmol). Subsequently, trichlorosilane (87.17 g, 643.5 mmol) was distilled into the ampoule using a vacuum line transfer system. The ampoule was placed in an oil bath and heated slowly to 40° C., at which temperature it was kept for 12 days. The excess trichlorosilane was removed in vacuo, and distillation of the product yielded 37.6 g (74.1% yield), b.p. 202°-20° C. at 0.001 mm Hg of n-octyl-tris-[3-(trichlorosilyl)propyl]silane.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:18]([C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:19]>>[CH2:18]([C:20]1([C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[O:35][C:2]2[CH:9]=[C:8]([CH:10]([OH:17])[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:19]
Reactant: N#Cc1ccc(C(O)c2cccnc2)cc1F
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Product: CCC1(c2cccc(Oc3cc(C(O)c4cccnc4)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
Using the procedure described in Example 2, the crude title compound was prepared starting with 2-fluoro-4-(hydroxy-pyridin-3-yl-methyl)-benzonitrile (as described in Step C above) (0.075 g, 0.329 mmol) and 3-ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (0.082 g, 0.329 mmol). Purification by preparative HPLC and conversion to the free base yielded the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[CH2:4][CH2:3]1.[H-].[Na+].C([O:27][C:28](=[O:30])[CH3:29])(C)(C)C.FC(F)(F)C(O)=O>O1CCCC1.C(OCC)(=O)C.ClCCl.O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][CH:5]2[CH2:6][CH2:7][CH:2]([O:1][CH2:29][C:28]([OH:30])=[O:27])[CH2:3][CH2:4]2)=[CH:10][C:11]=1[C:17]([F:18])([F:19])[F:20])#[N:14]
Reactant: N#Cc1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Reactant: CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(NC2CCC(OCC(=O)O)CC2)cc1C(F)(F)F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
4-(4-Hydroxy-cyclohexylamino)-2-trifluoromethyl-benzonitrile (4.30 mmol) is dissolved in dry tetrahydrofuran (10 mL) and sodium hydride (60% suspension in oil, 13.0 mmol) is added. The resulting mixture is stirred for 15 minutes and is cooled down to 5° C. prior to the addition of acetic acid tert-butyl ester (4.30 mmol). After 1.5 hours reaction time, water (7 mL) is slowly added under vigorous stirring and the mixture is then diluted with ethyl acetate (25 mL). The organic phase is collected and is concentrated under reduced pressure. The residue obtained is then treated with a 1 to 1 mixture of dichloromethane and trifluoroacetic acid (10 mL). After 2 hours, the reaction mixture is concentrated under reduced pressure. The residue obtained is taken up in dichloromethane (20 mL) and the organic phase is extracted with aqueous 3N sodium hydroxide solution (3×7 mL) and washed with water (2×5 mL). The pH of all combined aqueous phases is then brought to 5-6 by the addition of aqueous 5N hydrochloric acid. The acidic aqueous phase is extracted with dichloromethane (4×15 mL) and the combined organic layers are dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired acid (39% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:28](=[O:39])[CH2:29][CH2:30][C@H:31]([NH2:38])[CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:40]([C:43]1[C:44]([CH:56]=O)=[CH:45][C:46]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:47][CH:48]=1)([O-:42])=[O:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.CCOC(C)=O>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28](=[O:39])[CH2:29][CH2:30][C@H:31]([NH:38][CH2:56][C:44]2[C:43]([N+:40]([O-:42])=[O:41])=[CH:48][N:47]=[C:46]([O:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:45]=2)[CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCOCC1)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[[4-amino-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester (1.9 g, 3.5 mmol) and 5-nitro-2-phenoxy-pyridine-4-carboxaldehyde (0.86 g, 3.53 mmol) in 1,2 dichloroethane (100 mL) was stirred at room temperature for 4 hours, and then NaBH(OAc)3 (1.4 g, 6.6 mmol) was added. The resulting mixture was stirred at room temperature overnight. Then 1N NaOH was added, and the reaction mixture was then poured into EtOAc (200 mL). The organic layer washed with aq. NaCl, dried with MgSO4, filtered, and evaporated to yield a residue. The residue was purified by column chromatography (1:1 heptane/EtOAc) to yield 4-{(2-benzyloxy-ethyl)-[4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-amino}-cis-cyclohexanecarboxylic acid benzyl ester as an oil.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](Cl)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:39][O:40][C:41]1[CH:42]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[C:10]1[C:25]([CH3:26])=[CH:24][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:43]4[CH:44]=[N:45][CH:46]=[C:41]([O:40][CH3:39])[CH:42]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)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+]
Product: COc1cncc(-c2cc(-c3nc4cc(C)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(-c5ccc(Cl)cc5)c4s3)ccn2)c1
Temperature: 110 °C

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (40.0 mg, 0.070 mmol), 5-methoxy-3-pyridineboronic acid pinacol ester (19.7 mg, 0.084 mmol), potassium carbonate (29.0 mg, 0.210 mmol), and Pd(PPh3)4 (12.1 mg, 0.010 mmol) were placed in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (0.8 mL) and water (0.2 mL). The reaction mixture was heated at 110° C. for 1 h then cooled to rt. The aqueous layer was separated and extracted three times with ethyl acetate. All organic layers were combined, dried over Na2SO4, and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the product. LCMS-ESI+: calc'd for C36H39ClN3O4S: 644.2 (M+H+); Found: 644.1 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.81 (d, J=4.9 Hz, 1H), 8.40 (d, J=2.7 Hz, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.83 (d, J=5.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 4.83 (dd, J=9.4, 2.7 Hz, 1H), 4.43 (dd, J=11.2, 9.5 Hz, 1H), 4.30 (dd, J=12.1, 2.9 Hz, 1H), 3.99 (s, 3H), 2.81 (s, 3H), 1.15 (s, 9H), 0.97 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: Cc1cccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-methylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 320.0 (M+H)+, retention time 1.37 minutes.