Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])#[N:2].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[C:1]#[N:2])[C:7]1=[O:12]
Reactant: N#Cc1cccc2c1CCC2=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc2c1CC(Br)C2=O
Reaction time: 1 h
Yield: 33.1 %

Procedure:
2-Bromo-4-cyano-1-indanone can be obtained in the following way: a solution of 6.9 g of 4-cyano-1-indanone and 95 ml of chloroform is cooled to 5° C. A solution of 7.04 g of bromine and 20 ml of chloroform is then added dropwise over two hours at a temperature of between 0 and 5° C. After having left the reaction mixture stirring for one hour, the temperature of introduction being retained, the solution is allowed to return to room temperature and stirring is continued overnight. The reaction mixture is then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residue thus obtained is purified by flash chromatography on a silica column, under a nitrogen stream at medium pressure (0.5 bar), with an ethyl ether/cyclohexane (20/80 by volume) mixture as eluent. 3.43 g of 2-bromo-4-cyano-1-indanone are thus obtained, which product melts at 124° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](C(C2C(O)=CC3C(C)(C)CCC(C)(C)C=3C=2)=O)=[CH:6][CH:5]=1.[H-].[Na+].BrCCCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCBr
Product: COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 171.2 %

Procedure:
A solution of the 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (433 mg, 1.18 mmol) in DMF (2 mL) was treated with NaH (1.5 mmol) at 0° C. and allowed to warm to ambient temperature over 1 h. The yellow solution was cooled again to 0° C., and treated with a solution of bromobutane (119 mL, 1.30 mmol) in DMF (1 mL) and allowed to warm to ambient temperature and stirred for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated to give a colorless oil. Purification by silica gel flash chromatography (20:1=hexanes:Et2O) gave 4-[3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester 275 mg (55%) as a white solid: 1H NMR (400 MHz, CDCl3) δ8.07 (½ABq, J=8.2 Hz, 2H, ArH), 7.81 (½ABq, J=8.2 Hz, 2H, ArH), 7.44 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.95 (s, 3H, OCH3), 3.81 (t, J=6.2 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.34 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.27 (s, 6H, 2CH3), 1.02 (m, 2H, CH2), 0.71 (t, J=7.2 Hz, 3H, CH3); HRMS calcd. for C27H34O4 423.2535 (MH+), found 423.2505. The butyloxy keto ester (150 mg, 0.36 mmol) was hydrolyzed with excess KOH in MeOH as described in Example 1 to give 4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid (111) 82 mg (59%) as a white solid: mp 207-210° C.; 1H NMR (400 MHz, CDCl3) δ8.14 (½ABq, J=8.2 Hz, 2H, ArH), 7.84 (½ABq, J=8.2 Hz, 2H, ArH), 7.46 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.81 (t, J=6.2 Hz, 2H, OCH2), 1.71 (m, 4H, 2CH2), 1.32 (s, 6H, 2CH3), 1.29 (m, 2H, CH2), 1.28 (s, 6H, 2CH3), 1.00 (m, 2H, CH2), 0.72 (t, J=7.3 Hz, 3H, CH3); HRMS calcd. for C26H32O4 408.2301 (M+), found 408.2300.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[N+:11]([O-])([OH:13])=[O:12].[OH-].[K+]>S(=O)(=O)(O)O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Ic1ccc2nccn2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-iodoimidazo[1,2-α]pyridine (Intermediate 6, 448 mg, 1.84 mmol) in concentrated sulfuric acid (1.8 mL) at 15° C. was added concentrated nitric acid (0.54 mL) dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for one hour and was poured onto 10 g of ice. The pH of the mixture was adjusted to 4 with aqueous potassium hydroxide solution and the resultant solids were collected by filtration, washed with water and dried. The crude product was recrystallized from dichloromethane/hexanes to afford the title compound. LC/MS 289.8 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([O:15][CH2:16][CH:17]([NH:35][OH:36])[CH2:18][S:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[C:32]([Cl:34])[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(O)=O>[CH2:8]([O:15][CH2:16][CH:17]([N:35]([OH:36])[CH:1]=[O:3])[CH2:18][S:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[C:32]([Cl:34])[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(COCc1ccccc1)NO)N1CCN(c2cc(Cl)ncn2)CC1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(COCc1ccccc1)CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (31.5 ml) was added directly to formic acid (126 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1-{[3-benzyloxy-2-(hydroxyamino)propyl]sulphonyl}-4-(6-chloropyrimidin-4-yl)piperazine (29.5 g) in tetrahydrofuran (150 ml) and formic acid (25 ml), was added in portions to the above solution at 25° C. over 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (2×250 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO4), and evaporated to dryness. The residual foam was dissolved in methanol (70 ml) and the solution was stirred for 16 hours. The solution was evaporated to dryness (water-bath temperature 30° C.) The residual foam was stirred in ethanol (250 ml), solid separated and the mixture was stirred for 18 hours. The solid was collected by filtration, slurry washed with diethyl ether (100 ml), and dried to give N-[2-(benyloxy)-1-({[4(6-chloropyrimidin-4-yl)piperazino]sulphonyl}methyl)ethyl]-N-hydroxyformamide (25.5 g). mp 118-120° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([OH:31])[CH2:19][CH2:18][C@H:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([OH:31])[CH2:19][CH2:18][C@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1
Reactant: CC(C)[Si](O[C@H]1CC[C@](O)(c2cccc(F)c2F)Cc2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
In a 250 mL round-bottom flask was dissolved (6R,95)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-6-ol (977 mg, 2.183 mmol) in tetrahydrofuran (10 mL) to give a colorless solution. TBAF (4.80 mL, 4.80 mmol) was added, and the mixture was stirred at 50° C. overnight for 16 h. LCMS indicated good conversion with some SM left. Another 0.2 equiv of TBAF was added and the reaction continued at 50° C. for 2 h. Tetrahydrofuran was removed and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 10% methanol/methylene chloride afforded the desired product as a white solid (458 mg, 72%). MS(ESI)[M+H+]=292.21; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.05 (d, J=3.78 Hz, 1H) 7.37 (d, J=7.55 Hz, 1H) 7.06-7.21 (m, 1H) 6.81-7.05 (m, 3H) 5.63 (br. s., 1H) 4.82-4.97 (m, 1H) 3.68-4.11 (m, 2H) 3.00 (d, J=14.35 Hz, 1H) 2.77 (t, J=10.58 Hz, 1H) 2.13 (t, J=11.21 Hz, 1H) 1.87-2.03 (m, 1H) 1.69-1.86 (m, 1H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −137.37 (br. s., 1F) −137.99 (d, J=15.52 Hz, 1F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([NH:26][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NN1CCCCCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NN1CCCCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-azepan-1-yl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.45 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 6.2 mmol of azepan-1-ylamine. LC/MS [8.99 min; 455 (M+1)]
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]([CH2:15][O:16][CH2:17]C)=[CH:8][C:5]=1[CH:6]=O)([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]([CH2:15][O:16][CH3:17])=[CH:8][C:5]=1[CH:6]=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:2])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CCOCc1cc(C=O)c(C(C)C)cc1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCc1cc(C=Nc2ccccc2)c(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A solution of 10.36 g (44.3 mmol) of the compound from Example 5, 4.06 g (44.6 mmol) of freshly distilled aniline and 0.3 g of p-toluenesulphonic acid in 370 ml of toluene is heated under reflux for 1.5 h in a water separator (molecular sieve 4 Å), diluted with ethyl acetate after cooling to room temperature, washed with saturated sodium hydrogencarbonate solution and water, dried using sodium sulphate and concentrated in vacuo.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])[C:10]1[C:11]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]1[N:41]=[N:42][N:43]=[C:15]1[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 90 °C
Yield: 23.9 %

Procedure:
The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26)(30 mg) and sodium azide (32 mg) in DMF (1 mL) was heated at 90° C. for 4 hours. The mixture was diluted with ethyl acetate, and washed with water and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-yl)ethyl pivalate (5.9 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H32ClN4O3: 495.2. Found: 495.2.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1cccc(C(Cl)Cn2ccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
144 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to a solution of 555 mg of methyl 4-mercaptobenzoate in 4 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 710 of 1-[2-chloro-2-(3-methoxyphenyl)ethyl]imidazole in 3 ml of dry dimethylformamide was added to this solution, and the reaction mixture was heated at 60°-70° C. for 5.5 hours. At the end of this time, the resulting mixture was treated and purified according to the same procedure as described in Example 1, to give 631 mg of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][O:22][CH:23]([C:27]2[C:35]3[C:31](=[CH:32][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:34]=3)[CH:30]=[C:29]([Cl:44])[CH:28]=2)[C:24](O)=[O:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][NH:46][CH3:47].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Cl:44][C:29]1[CH:28]=[C:27]([CH:23]([O:22][CH2:21][C:11]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[C:24]([N:46]([CH3:47])[CH3:45])=[O:25])[C:35]2[C:31](=[CH:32][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:34]=2)[CH:30]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 1 h

Procedure:
To a solution of 2-((1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methoxy)-2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetic acid (25 mg, 0.039 mmol) and dimethylamine (40% in water, 0.024 mL) in dimethylformamide (1 mL) at 0° C. was added PyBOP® (24.08 mg, 0.046 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of water and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (50%→85% ethyl acetate/n-hexane) gave 21 mg (81%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.5, 5.5 Hz, 2H), 7.09 (d, J=1.8 Hz, 1H), 6.99 (dd, J=8.6, 8.5 Hz, 2H), 5.66 (d, J=10.7 Hz, 1H), 5.62 (d, J=10.7 Hz, 1H), 3.70 (m, 2H), 3.57 (m, 3H), 3.44 (d, J=8.9 Hz, 1H), 3.05 (m, 2H), 2.88 (s, 3H), 2.80 (s, 3H), 2.13 (m, 2H), 1.91 (m, 2H), 1.42 (s, 9H), 0.91 (t, J=8.3 Hz, 2H), −0.04 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 169.0, 161.5 (d, J=245 Hz), 155.0, 145.8, 138.7, 129.0 (d, J=7.7 Hz), 128.3, 125.9, 122.7, 122.5, 119.2, 115.2 (d, J=21 Hz), 82.1, 79.4, 78.4, 75.7, 67.7,41.4, 40.1 (br), 36.8, 36.1, 32.1, 28.6, 17.9, −1.3. Mass spec.: 675.38 (MH)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][C:30](=[O:32])[C:29]5([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[N:28]=4)=[CH:23][CH:22]=3)[N:20]=2)[CH2:12][CH2:11]1>CN(C)C=O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:28][C:29]4([C:30]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:32])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]4)=[O:31])=[CH:25][CH:26]=3)[N:20]=2)[CH2:12][CH2:11]1
Reactant: CN1CCN(c2nc(-c3ccc(C4=NC5(CCCCC5)C(=O)O4)cc3)cs2)CC1
Reactant: CSCC[C@H](N)CO
Solvent: CN(C)C=O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
100 mg (0.74 mmol) of L-methioninol was added to a solution of 250 mg (0.68 mmol) of 2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 20 ml of dimethylformamide. After the mixture was stirred at 80° C. for 15 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue to wash the crystal to obtain 319 mg (86%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([C:20]#[N:21])=[CH:4][N:3]=1.[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH2:36])=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH:36][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:17][CH:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([C:20]#[N:21])=[CH:4][N:3]=3)=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC2CCCN21
Reactant: Nc1cc(-n2cnnn2)c(C2CC2)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4cnnn4)c(C4CC4)cc3F)ncc2C#N)CC2CCCN21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (±)-2-chloro-4-(octahydro-5,5-dimethylindolizin-7-ylamino)pyrimidine-5-carbonitrile (60 mg of 70% pure material from previous step), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzeneamine (65 mg, 0.3 mmol; prepared according to U.S. patent application Ser. No. 13/188,222, filed Jul. 21, 2011, now U.S. patent application publication US2012/0022092) and para-toluenesulfonic acid monohydrate (37 mg, 0.2 mmol) in isopropyl alcohol (3 ml) were combined in a sealed vial, heated to 80° C. and stirred for 4 hours. After cooling, a precipitate emerged which was filtered. The filter cake was suspended in EtOAc (30 ml) and 1N NaOH (50 ml). The aqueous and organic layers were partitioned and the aqueous layer was extracted with EtOAc (2×25 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed under vacuum to leave a solid. The solid was freeze-dried from MeCN/H2O to give the product (26 mg) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10]([C:14]1[N:15]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:16]=[C:17]([Sn](CCCC)(CCCC)CCCC)[N:18]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[N:15]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:16]=[C:17]([C:2]2[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=2)[C:8]#[N:9])[N:18]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CC2CCOCC2)c(C(C)(C)C)n1
Reactant: N#Cc1ccnc(Cl)c1
Product: CC(C)(C)c1nc(-c2cc(C#N)ccn2)cn1CC1CCOCC1

Procedure:
The title compound 124 (70 mg, 0.22 mmol, yield: 68%) was obtained in the same manner as in step 3 of Example 101, using 2-chloro-4-cyanopyridine and 2-tert-butyl-1-(tetrahydropyran-4-yl)methyl-4-tributylstannyl-1H-imidazole obtained in step 1 of Example 108.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[C:16]([C:18]1[CH:19]=[C:20]([C:25]2[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=2)[CH:21]=[CH:22][C:23]=1O)#[N:17]>N1C=CC=CC=1>[C:16]([C:18]1[CH:19]=[C:20]([C:25]2[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=2)[CH:21]=[CH:22][C:23]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])#[N:17]
Reactant: COC(=O)c1ccc(-c2ccc(O)c(C#N)c2)s1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)s1
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride was added to a pyridine solution of methyl 5-(3-cyano-4-hydroxyphenyl)thiophene-2-carboxylate and the whole was stirred at room temperature to obtain methyl 5-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)thiophene-2-carboxylate. F: 392.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:38]([C:29]3[CH:30]=[CH:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]=3)=[O:39])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(NC2CCN(C(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Compound (49) (0.056 g, 0.2 mmol) and triethylamine (0.14 mL, 1 mmol) were added sequentially to a solution of 2-naphthoyl chloride (0.114 g, 0.6 mmol) in CH2Cl2 (5 mL) at 25° C. The mixture was stirred at 25° C. for 12 h, then was concentrated in vacuo to a residue. Purification of the residue by flash column chromatography (gradient elution 5 to 30% EtOAc in hexanes) provided the title compound (0.04 g, 50%): TLC (Rf =0.50; 50% EtOAc/hexanes); 1H NMR (CDCl3) δ 7.84 (m, 6H), 7.51 (m, 3H), 6.55 (d, 2H, J=8.8), 4.65 (br s, 1H), 4.01 (d, 2H, J=7.8), 3.66 (m, 1H), 3.18 (t, 2H, J=11.2), 2.05 (m, 2H), 1.56 (s, 9H), 1.46 (m, 2H); 13C NMR (CDCl3) δ 170.5, 166.0, 150.1, 133.8, 133.3, 132.9, 131.5, 128.4, 127.9, 127.8, 127.1, 126.8, 124.2, 121.1, 111.9, 79.9, 49.9, 32.6, 28.4; HRMS (FAB) m/z 430.2241 (M)+ (C27H30N2O3 requires 430.2256).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:34]([CH:12]([C:10]1[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[5-chloro-8-(2-fluorophenyl)quinolin-7-yl]ethanol (0.044 g, 0.14 mmol) in methylene chloride (0.9 mL) was added triethylamine (0.0305 mL, 0.219 mmol), followed by methanesulfonyl chloride (0.0141 mL, 0.182 mmol). After stirring at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting residue was used directly in next step. LCMS (M+H)+m/z=380.0. The crude mesylate was dissolved in N,N-dimethylformamide (0.4 mL) and treated with sodium azide (0.0474 g, 0.730 mmol) at 60° C. for 1 hour. After diluting with ethyl acetate, the mixture was washed with water and brine and then dried over magnesium sulfate and evaporated to dryness. The crude product was used in the next step. LCMS calculated for C17H13ClFN4(M+H)+: m/z=327.1; found: 327.0.