Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:29])[C:8]1=[O:30])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[CH2:22]([C:14]1[C:11]2[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:30])[N:9]([CH3:29])[C:10]=2[N:17]=[CH:16][C:15]=1[O:18][CH:19]([CH3:21])[CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)Oc1cnc2c(c1Cc1ccccc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cnc2c(c1Cc1ccccc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.6 %

Procedure:
To a solution of 3-(5-benzyl-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (70 mg, 0.17 mmol) in THF (1 mL) and water (1 mL) was added LiOH.H2O (14.2 mg, 0.34 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-benzyl-3-(3-hydroxypropyl)-6-isopropoxy-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (18 mg, 39.0% yield) as a white solid. 1H NMR (CDCl3) δ: 8.32 (s, 1H), 7.25-7.18 (m, 4H), 7.17-7.10 (m, 1H), 4.78 (s, 2H), 4.62 (dt, J=12.1, 6.1 Hz, 1H), 4.26-4.15 (m, 2H), 3.69 (s, 3H), 3.52-3.43 (m, 2H), 3.17 (t, J=7.0 Hz, 1H), 1.94-1.82 (m, 2H), 1.34 (d, J=6.0 Hz, 6H). LCMS: MH+ 384 and TR=2.708 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH:20][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: COc1ccc(Cl)c(N)c1
Product: COc1ccc(Cl)c(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 60.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-chloro-5-methoxyaniline (109 mg, 0.56 mmol) to provide 208 (92 mg, 60% yield) as a white solid. LC-MS (M+H=352, obsd.=352).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C@H:14]([Cl:29])[C@H:13]3O)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC)(OC)OC.O>ClCCl>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14]([Cl:29])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
5.0 g of 17α-acetoxy-6β-chloro-7α-hydroxy-1α,2α-methylene-4-pregnene-3,20-dione is mixed in 25 ml of dichloromethane with 0.1 g of p-toluenesulfonic acid and 3.0 ml of trimethyl orthoformate. The mixture is allowed to stand for 4 hours at 0° C., mixed with 20 ml of water and stirred for 15 minutes. Then the organic phase is separated, dried with sodium sulfate and concentrated in vacuo. Thus, 4.8 g of 17α-acetoxy-6-chloro-1α,2α-methylene-4,6-pregnadiene-3,20-dione with a melting point of 202° to 205° C. (80% purity) is obtained.
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11])=[O:4]>C(Cl)Cl.CO>[OH:4][CH2:3][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1ccccc1C1CC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccccc1C1CC1CO
Reaction time: 2 h

Procedure:
Solid sodium borohydride (110 mg, 2.92 mmol) was added portionwise to a solution of 2-(2-formylcyclopropyl)benzonitrile (500 mg, 2.92 mmol) in methylene chloride (6 mL) and MeOH (10 mL). The mixture was stirred for 2 hr. The reaction was concentrated, and the residue was dissolved in ether and water. The ether layer was separated, washed with water and brine, dried over magnesium sulfate, and concentrated to give 2-(2-(hydroxymethyl)cyclopropyl)benzonitrile as a slightly colored wax (425 mg, 84%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.63 (dd, J=7.7, 0.9 Hz, 1H), 7.52 (td, J=7.8, 1.0 Hz, 1H), 7.36-7.24 (m, 1H), 7.08 (d, J=8.0 Hz, 1H), 3.87-3.72 (m, 1H), 3.65 (dd, J=11.2, 7.2 Hz, 1H), 2.25-2.13 (m, 1H), 1.82 (br. s., 1H), 1.60 (s, 1H), 1.56-1.45 (m, 1H), 1.12 (ddt, J=15.3, 8.6, 5.3 Hz, 1H). LCMS: M+1=173.1.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17]1[O:20][C@H:18]1[CH3:19].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:17][C@H:18]([OH:20])[CH2:19][O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: C[C@H]1CO1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@H](O)COc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of 4-phenoxyphenol (2.14 g, 11.5 mmol) in toluene (7 ml) was poured into an aqueous solution (3 ml) of sodium hydroxide (0.92 g, 23.0 mmol), and (S)-(-)-propylene oxide (1.0 g, 17.24 mmol; a reagent manufactured by Aldrich; [α]D20 =-7.2°(CHCl3, c=1)) was added thereto while stirring. To the resultant mixture, tetra-n-butylammonium bromide (185 mg) was added, and the mixture was stirred at room temperature for 12 hours, followed by addition of (S)-(-)-propylene oxide (1 g). After stirring at room temperature for 6 hours, the reaction mixture was vigorously stirred with addition of water (20 ml) and toluene (20 ml). The toluene layer was separated and washed with a 20% aqueous sodium hydroxide solution and an aqueous sodium chloride solution in order and dried over magnesium sulfate. Removal of the solvent gave crude (S)-(+)-1-methyl-2-(4-phenoxyphenoxy)ethanol (2.35 g), which was further purified by silica gel column chromatography to give (S)-(+)-1-methyl-2-(4-phenoxyphenoxy)ethanol (1.97 g). [α]D23 =+14.0°(CHCl 3, c=1). ee.; 72.9%.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15]CCC.CI.Cl>C1COCC1>[CH3:15][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: CC1c2ccccc2-c2ccccc21
Temperature: -70 °C
Yield: 67.6 %

Procedure:
A mixture of fluorene (78.3 g) and THF (700 mL) was cooled down to −70° C., and n-BuLi (300 mL, corresponding to 0.48 mol) was dropwise added thereto while maintaining −60° C. or lower. Then, methyl iodide (66.8 g) was added, and the temperature was allowed to slowly go back to a room temperature. The mixture was cooled again down to 0° C. to add 3M-hydrochloric acid (300 mL), and the reaction mixture was extracted with toluene. The organic layer obtained was washed well in order with saturated sodium hydrogencarbonate, saturated sodium hydrogensulfite and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the residue was purified by means of column chromatography (silica gel, eluting solvent: toluene/heptane [40/60]) and recrystallization (ethanol) to obtain 9-methylfluorene (57.4 g) of pale yellow crystal. Melting point: 47.3-48.8° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:20]([OH:22])=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1cc(C(=O)N(C)c2cnccc2-c2ccccc2C)cc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 2-chloro-6-methylisonicotinic acid (CAS RN 25462-85-5) after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (7%). MS (ESI): m/z=352.12 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](O)=[O:15])=[CH:8][C:6]=2[N:7]=1.[NH2:26][CH2:27][C@@H:28]([OH:30])[CH3:29]>>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([NH:26][CH2:27][C@@H:28]([OH:30])[CH3:29])=[O:15])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg) was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide. 3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide (56 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 24.8 mg of 336. MS (Q1) 515.2 (M)+
Reaction SMILES: [H-].[Na+].[CH2:3]([S:5][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:4].CI.[C:27](=O)(O)[O-].[Na+]>O.C1COCC1>[CH2:3]([S:5][C:6]1[C:7]([C:12]([N:14]([CH3:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CCSc1cccnc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.9 g of 60% sodium hydride (oil-based) was added to a mixture of 0.65 g of 3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (Compound of Present Invention 2) and 4 mL of THF under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was ice-cooled, 1.0 g of methyl iodide was added thereto, and then the mixture was stirred at 30° C. for 2 hours. Water and a saturated aqueous sodium bicarbonate solution were poured to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.27 g of 3-ethylsulfanyl-N-methyl-N-(5-trifluoromethyl-pyridin-2-yl) picolinamide (hereinafter, referred to as Compound of Present Invention 16).
Reaction SMILES: [CH:1]1([C:4]([OH:12])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:3][CH2:2]1.N1C=CN=C1.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[CH:1]1([C:4]([O:12][Si:19]([CH3:22])([CH3:21])[CH3:20])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])[CH2:2][CH2:3]1
Reactant: C#CCC(O)(CCCC)C1CC1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of 27.8 g of 4-cyclopropyl-4-hydroxy-1-octyne (Example 190) and 33.3 g of imidazole in 130 ml of dimethylformamide at 5° C. is added 24 ml of chlorotrimethylsilane during 5 minutes. The solution is stirred at ambient temperature for 17 hours and then partitioned with 600 ml of hexane and 250 ml of ice water. The hexane phase is separated and washed successively with water and brine. The solution is dried over magnesium sulfate and evaporated to give a liquid, pmr spectrum (CDCl3): δ0.12 (singlet, trimethylsiloxy group), 2.02 (triplet, HC≡C), and 2.45 (doublet, C≡CH2).
Reaction SMILES: FC(F)(F)C(N1C[C@H](C)C2C=C(Cl)C=CC=2CC1)=O.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]([CH3:31])[C:25]=2[C:32]=1[Cl:33]>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]([CH3:31])[C:25]=2[C:32]=1[Cl:33]
Reactant: C[C@@H]1CNCCc2ccc(Cl)c(Cl)c21
Agent: C[C@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Product: C[C@H]1CNCCc2ccc(Cl)c(Cl)c21

Procedure:
Compound,7 was prepared from (R)-N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizing a similar two step procedure as described herein for the preparation of Compound 5. 1H NMR (400 MHz, CDCl3) δ 7:40 (d, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 4.17 (m, 1H), 3.55 (m, 2H), 3.5-3.3 (m, 2H), 3.2-3.0 (m, 2H), 1.43 (d, J=7 Hz, 3H). MS calculated for C11H13Cl2N+H: 230, observed: 230.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:34]=[C:33]5[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]5)=[CH:27][CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=1[C:39](Cl)=[O:40]>C1COCC1.CO>[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=1[C:39]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:34]=[C:33]5[C:28]([CH2:29][CH2:30][N:31]([CH3:35])[CH2:32]5)=[CH:27][CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:40]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CN1CCc2ccc(Nc3ncc(F)c(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)cc2C1
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCc2ccc(Nc3ncc(F)c(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.1 %

Procedure:
To a solution of N-{4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-5-fluoro-2-pyrimidinyl}-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (50 mg, 0.11 mmol) in THF (5 mL) was added 2,6-difluorobenzoyl chloride (20 mg, 0.11 mmol) and the reaction mixture stirred at rt for 20 min. The reaction was diluted with MeOH, adsorbed to silica gel, and purified by column chromatography (0-10% MeOH/DCM+1% NH4OH) to afford the title compound (15.4 mg, 24%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.52 (s, 1H), 8.86 (d, J=7.69 Hz, 1H), 8.45-8.46 (m, 1H), 8.06 (s, 1H), 7.89 (d, J=8.61 Hz, 1H), 7.71-7.73 (m, 1H), 7.54-7.58 (m, 1H), 7.30-7.47 (m, 4H), 7.20-7.24 (m, 3H), 7.08-7.12 (m, 1H), 6.86 (d, J=8.42 Hz, 1H), 3.26 (s, 2H), 2.66-2.69 (m, 2H), 2.49-2.51 (m, 2H), 2.26 (s, 3H); ESIMS (M+H)+=606.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18]([C:20]3[C:21]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:14]=2)[CH2:9]1)(C)(C)C>C(O)=O>[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18]([C:20]3[C:21]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2C1
Solvent: O=CO
Product: NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the title E compound ({5-[(4′-trifluoromethylbiphenyl-2-carbonyl)-amino]indan-2-yl}-carbamic acid tert-butyl ester, 5.19 g, 10.5 mmol) in formic acid (40 mL) is heated to 40° C. with stirring. After 3 h, the reaction mixture is cooled to room temperature and stirring is continued for 16 h. The reaction mixture is concentrated under reduced pressure and the resulting oil dissolved in ethyl acetate. The organic layer is washed with 8% NaHCO3 solution until the aqueous layer remains basic at which point a precipitate forms in the organic layer. The precipitate is collected by filtration to give 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide. The organic layer of the filtrate is dried (MgSO4) and concentrated under reduced pressure to give a solid. Trituation of the solid with diethyl ether yields additional 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][N:18]=3)[CH:5]=[CH:4][C:3]1=2.CCCCCCC>C1COCC1.[OH-].[Na+]>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)O)cn3)ccc21
Yield: 35.7 %

Procedure:
In a manner similar to that of Example 7, by reaction of 600 mg (1.36 mmol) of ethyl 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate in 30 ml of THF and 1 g of sodium hydroxide, and after trituration from heptane, 200 mg (36%) of the expected compound are obtained in the form of a yellow solid. m.p.=128° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].CN1CCOCC1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH2:15]([O:22][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=C(Cl)CCCBr
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=C(CCCBr)OCc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
In the first step, 4-bromobutyryl chloride (13.8 g, 75 mmole) was placed in a 100 ml round bottom flask. The flask was cooled to -20° C. using a dry ice/carbon tetrachloride bath. Ethyl acetate (50 ml) containing N-methylmorpholine (7.58 g, 75 mmole, 8.2 ml) was added carefully. Using an addition funnel, benzyl alcohol (6.97 g, 6.67 ml, 6.64 mmoles) was added dropwise. After the addition the bath was removed and the mixture was stirred for 2 hours. The product was transferred to a separatory funnel using ethyl acetate (50 ml), washed once with sodium bicarbonate (10%), then twice with water, and dried with anhydrous sodium sulfate. Evaporation of solvents gave benzyl-4-bromo-butyrate as an oil (yield=91%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.CNC.C(O)C.Br[CH2:20][C:21]([NH:23][C:24]1[S:25][C:26]([C:34]([CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:35])=[C:27]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:22]>C1COCC1.C(OCC)C>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:27]1[N:28]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][N:10]2[CH2:11][CH2:12][N:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH2:8][CH2:9]2)[S:25][C:26]=1[C:34]([CH:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1)=[O:35]
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CNC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(CN1CCN(C2CCOCC2)CC1)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Yield: 54 %

Procedure:
In a manner similar to that in Example 533, by using 1-(tetrahydropyran-4-yl)piperazine (154 mg, 9.00 mmol) in place of the solution of dimethylamine in THF, followed by reslurrying with a mixed solvent of ethanol and diethyl ether, the entitled Compound 571 (79.8 mg, 54%) was obtained from Compound 531; (120 mg, 0.300 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11](COCC[Si](C)(C)C)[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[C:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[N:39]1[CH2:40][CH2:41][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][CH2:38]1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(N3CCC(c4ccccc4)CC3)c(Cl)cc2[nH]1
Temperature: 90 °C

Procedure:
A 2 dram vial was charged with (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (Intermediate 3, 300 mg, 0.542 mmol), 4-phenylpiperidine (96 mg, 0.596 mmol), L-proline (12.47 mg, 0.108 mmol), cuprous iodide (10.32 mg, 0.054 mmol), potassium carbonate (150 mg, 1.083 mmol), and DMSO (1354 μl). The reaction vial under nitrogen was placed in a heating block set to 70° C. and then heated to 90° C. for 16 hours. The reaction was cooled to r.t. and diluted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified via silica gel chromatography using methanol/dichloromethane to afford the title compound as an orange waxy solid. LC-MS: calculated for C29H39ClN4O5Si 586.24 observed m/e: 587.44 (M+H)+ (Rt 1.41/2 min).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:22]([CH3:33])[C:21]=1[CH3:34]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([CH3:33])[C:21]=3[CH3:34])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2csnc2-c2ccc(Cl)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-chlorophenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.70 (d, J=7.5 Hz, 2H), 7.42 (d, J=7.5 Hz, 2H), 6.98 (d, J=7.6 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 5.05 (s, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 2.24 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccccc1Br
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccccc1-c1ccco1

Procedure:
To a solution of 2-bromoaniline (137 mg, 0.80 mmol) in THF (4.0 ml) was added 2-furanboronic acid (89 mg, 0.80 mmol), tetrakis-(triphenylphosphine)palladium (0) (92 mg, 0.08 mmol) and sodium carbonate solution (2M, 2.0 ml, 4.0 mmol). The mixture was heated in a sealed tube using a microwave reactor (20 W) at 130° C. for 25 min. This procedure was carried out 5 times and the reaction mixtures were combined. The mixture was separated and the aqueous layer extracted with EtOAc. The combined organic layers were dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant pet. ether:EtOAc 85:15) to give a brown oil; yield 211 mg, 33%.