Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([Br:13])=[CH:8][C:7]=1[Cl:14].[F:18][C:19]1([F:27])[CH2:24][CH2:23][C:22]([CH3:26])([OH:25])[CH2:21][CH2:20]1>C(Cl)Cl.C1CCCCC1.FC(F)(F)S(O)(=O)=O>[Br:13][C:9]1[CH:8]=[C:7]([Cl:14])[C:6]([CH2:5][O:25][C:22]2([CH3:26])[CH2:23][CH2:24][C:19]([F:27])([F:18])[CH2:20][CH2:21]2)=[CH:11][C:10]=1[F:12]
Reactant: N=C(OCc1cc(F)c(Br)cc1Cl)C(Cl)(Cl)Cl
Reactant: CC1(O)CCC(F)(F)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC1(OCc2cc(F)c(Br)cc2Cl)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 56 h
Yield: 18.1 %

Procedure:
To a solution of 4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate (4.00 g, 10.40 mmol) and 4,4-difluoro-1-methylcyclohexanol (1.21 g, 8.05 mmol) in methylene chloride (50 mL) and cyclohexane (25 mL) was added trifluoromethanesulfonic acid (0.1 mL, 0.14 mmol) at 0 ?C. The reaction mixture was stirred for 56 hours at ambient temperature and quenched by addition of saturated sodium bicarbonate solution (10 mL), and then diluted with methylene chloride (100 mL). The organic layer was separated and washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) and recrystallization from methanol afforded the title compound (0.54 g, 17%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=6.0 Hz, 1H), 7.30 (d, J=9.3 Hz, 1H), 4.37 (s, 2H), 2.11-1.86 (m, 6H), 1.72-1.59 (m, 2H), 1.26 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:7](=[O:18])[C:6](=[O:19])[NH:5]2.[CH3:20][C:21](=O)[CH2:22][CH2:23][C:24](=O)[CH3:25]>C(O)(=O)C>[Cl:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:19])[C:7](=[O:18])[N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3][C:2]=1[N:1]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]1[CH3:20]
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(N)c(Cl)cc21
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(-n3c(C)ccc3C)c(Cl)cc21
Temperature: 0 °C
Yield: 75.3 %

Procedure:
6.0 g (20.2 mmol) of 6-amino-7-chloro-1-(methoxycarbonylmethyl)-2,3(1H,4H)-quinoxalinedione and 2.4 ml (20.2 mmol) of 2,5-hexanedione were refluxed in 75 ml of glacial acetic acid for 0.5 h. The mixture was then poured into ice-water and the precipitate was filtered off with suction to yield 5.5 g (74%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cncc1Cl

Procedure:
A mixture of 3,5-dichloroisonicotinic acid (2.88 g, 15 mmol) and thionyl chloride (30 ml) was heated to reflux. A few drops of DMF were added and the suspension refluxed for 2 h to give a slightly yellow solution. Excess reagent was removed under reduced pressure and the residue azeotroped with toluene (2×50 ml) to give 3,5-dichloroisonicotinoyl chloride. This was dissolved in CH2Cl2 (50 ml) and added to a solution of 4-aminobenzyl alcohol (1.60 g, 13 mmol) and NMM (1.65 ml, 15 mmol) in CH2Cl2 (50 ml). The mixture was stirred at room temperature overnight. Manganese IV oxide (activated, <5 micron, ˜85%, 22 g) was added to the resulting suspension. The mixture was stirred at room temperature for 6 h then filtered through Celite®. The filtrate was washed with dilute hydrochloric acid (1M, 50 ml) and saturated aqueous sodium hydrogen carbonate (50 ml), dried (Na2SO4) and evaporated under reduced pressure to give the title compound (2.40 g, 63%) as a pale yellow solid. δH (DMSO-d6) 11.35 (1H, s, CHO), 9.95 (1H, s, CONH), 8.83 (2H, s, pyH), 7.96 (2H, d, J 8.7 Hz, ArH) and 7.88 (2H, d, J 8.7 Hz, ArH); m/z (ESI, 60V) 295 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21](O)([CH3:23])[CH3:22])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3=[C:13]([C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]2([CH3:23])[CH3:22])[CH:14]=1
Reactant: CC(C)(O)c1ccccc1-n1c2ccccc2c2cc(Br)ccc21
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(Br)cc1c32
Temperature: 60 °C

Procedure:
16.3 g (44 mmol) of 2-[2-(3-bromocarbazol-9-yl)phenyl]propan-2-ol are dissolved in 1200 ml of degassed toluene, a suspension of 40 g of polyphosphoric acid and 28 ml of methanesulfonic acid is added, and the mixture is heated at 60° C. for 1 h. The batch is cooled, and water is added. A solid precipitates out and is dissolved in CH2Cl2/THF (1:1). The solution is carefully rendered alkaline using 20% NaOH, and the phases are separated and dried over MgSO4. The solid obtained is washed by stirring with heptane. Yield: 13.5 g (37 mmol), 87% of theory, purity according to 1H-NMR about 95%.
Reaction SMILES: [NH:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:2][CH2:3][C:4]#[N:5].CO.C([BH3-])#N.[Na+].[C:16](#N)[CH3:17]>>[C:4]([CH2:3][CH2:2][N:1]([CH2:6][CH2:7][C:8]#[N:9])[CH2:16][CH3:17])#[N:5]
Reactant: N#CCCNCCC#N
Reactant: CC#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CCC#N)CCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a stirred mixture of 3,3'-iminodipropionitrile (14.4 g, 0.117 mol), acetaldelyde (25.7 g, 0.584 mol), methanol 50 mL), and acetonitrile (400 mL) was added sodium cyanoborohydride (9.6 g, 0.152 mol). The mixture was allowed to stir at room temperature overnight. The solvent was evaporated. The resulting residue was partitioned between dichloromethane and H2O. The dichloromethane layer was washed with water, dried, and evaporated to give a yellow oil, which was distilled by a Kugelrohr apparatus to give the title compound (9.2 g, 52%). 1H NMR (CDCl3, 200 MHz) 2.86 (t, J=7.0 Hz, 4H), 2.64 (q, J=7.0 Hz, 4H), 2.48 (t, J=7.0 Hz, 4H), 1.08 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Cl:26])=O)C1C=CC=CC=1.[N:27]1[C:36]2[C:31](=[N:32][C:33]([CH:37]=O)=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.N1CCCCC1>CC(O)C>[Cl:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:37][C:33]2[CH:34]=[CH:35][C:36]3[C:31](=[CH:30][CH:29]=[CH:28][N:27]=3)[N:32]=2)[C:14](=[O:16])[N:13]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(F)cc2Cl)=N1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccc(F)cc2Cl)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 2-(2-chloro-4-fluoro-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (70.1 mg, 0.19 mmol), 1,5-naphthyridine-6-carboxaldehyde (28.7 mg, 0.18 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-1,5-dihydro-imidazol-4-one as a light yellow solid, 30.6 mg (43.0%). HR-ES (+) m/e calcd. for C19H13FClN5O: (M+H)+ 382.0866. Found: 382.0866.
Reaction SMILES: [F:1][C:2]1[C:3]([O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:4][C:5]2[NH:9][C:8]([C:10]3[C:14]([N+:15]([O-])=O)=[CH:13][N:12]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[N:11]=3)=[N:7][C:6]=2[CH:24]=1.[H][H]>CO.[Pd]>[CH3:31][N:29]([CH3:30])[CH2:28][CH2:27][CH2:26][O:25][C:3]1[C:2]([F:1])=[CH:24][C:6]2[N:7]=[C:8]([C:10]3[C:14]([NH2:15])=[CH:13][N:12]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[N:11]=3)[NH:9][C:5]=2[CH:4]=1
Reactant: CN(C)CCCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])nc2cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3N)nc2cc1F
Yield: 93.4 %

Procedure:
A suspension of 2.3 g of (3-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yloxy}propyl)dimethylamine in 40 mL of methanol and 0.2 g of palladium-on-charcoal is hydrogenated under 1 bar of hydrogen pressure at ambient temperature for 18 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 2.0 g of 3-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine are obtained in the form of a brown solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.46 to 2.21 (m, 8H); 2.17 (s, 6H); 2.40 (t, J=7.0 Hz, 2H); 3.63 (m, 1H); 3.95 (m, 1H); 4.08 (m, 2H); 4.92 (broad s, 2H); 5.32 (dd, J=2.5 and 10.0 Hz, 1H); from 7.01 to 7.47 (m, 2H); 7.31 (s, 1H); 12.55 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]=[C:13]=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([CH3:27])[N:20]=[C:21]2[CH3:26].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH:12][C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[C:19]([CH3:27])[N:20]=[C:21]3[CH3:26])=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(N)cccc2c(C)n1
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(C)(C)C)cc3)cccc2c(C)n1

Procedure:
The product from Example 186A (3.42 mmol) in toluene (12 mL) was treated with 5-amino-1,3-dimethylisoquinoline (245 mg, 1.42 mmol) and DIEA (5 mL). The mixture was heated at 800 for 3 hours, cooled to room tempoerature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.21 (d, 1H, J=7.1 Hz), 7.78 (d, 1H, 8.5 Hz), 7.59 (s, 1H), 7.48 (t, 1H, J=8.0 Hz), 7.36-7.40 (m, 2H), 7.27-7.29 (m, 2H), 6.98 (m, 1H), 4.31 (d, 2H, J=5.8 Hz), 2.84 (s, 3H), 2.58 (s, 3H), 1.28 (s, 9H); MS (ESI+) m/z 362 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10]([C@@H:12]1[C@@H:16]([N:17]=[N+:18]=[N-:19])[C@@H:15]([OH:20])[C@H:14]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][CH:24]=[N:25][C:26]=3Cl)[O:13]1)=[O:11].[C:31]([O:35][C:36](=[O:48])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1[CH2:46][NH2:47])([CH3:34])([CH3:33])[CH3:32]>C(O)C>[C:31]([O:35][C:36](=[O:48])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=1[CH2:46][NH:47][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[C:27]=1[N:28]=[CH:29][N:21]2[C@H:14]1[C@H:15]([OH:20])[C@H:16]([N:17]=[N+:18]=[N-:19])[C@@H:12]([C:10](=[O:11])[NH:9][CH3:8])[O:13]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC(=O)OC(C)(C)C)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Temperature: 70 °C
Yield: 81.3 %

Procedure:
Triethyl amine (0.3 mL, 2.1 mmol) was added to a solution of (2S,3S,4R,5R)3-azido-5-(6-chloro-purin-9-yl)-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide (302 mg, 0.9 mmol) and 2-aminomethyl-4-chloro-phenoxy acetic acid tert-butyl ester (290 mg, 1.07 mmol) in ethanol at ambient temperature. The reaction was heated to 70° C. for 2.5 hours, cooled, and the resultant solid was washed with cold ethanol, and dried to afford 420 mg (81%) of the title compound as a colorless solid. Alternatively, the product could be purified by flash chromatography (2-5% methanol/dichloromethane). MS 574 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.28 (bs, 1H); 8.24 (s, 1H); 7.32 (bs, 1H); 7.18 (dd, 1H, J=8.9, 2.6 Hz); 6.92 (d, 1H, J=8.9 Hz); 5.95 (d, 1H, J=7.1 Hz); 5.03 (dd, 1H, J=7.1, 4.9 Hz); 4.82 (bs, 2H); 4.83 (s, 2H); 4.39 (m, 2H); 3.0 (s, 1H); 2.8 (s, 3H); 1.4 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:4]=1[C:5]([O:7]C)=O.[NH2:16][CH2:17][C:18]1[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=1[CH3:24]>CO>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][N:16]1[CH2:2][C:3]2[C:4](=[CH:9][C:10]([O:13][CH2:14][CH3:15])=[CH:11][CH:12]=2)[C:5]1=[O:7]
Reactant: CCOc1ccc(CBr)c(C(=O)OC)c1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Solvent: CO
Product: CCOc1ccc2c(c1)C(=O)N(Cc1c(C)cc(C)[nH]c1=O)C2
Temperature: 80 °C
Yield: 4.5 %

Procedure:
To a solution of methyl 2-(bromomethyl)-5-ethoxybenzoate (134c, 0.636 g, 2.33 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (Cpd V, 0.390 g, 2.56 mmol) in MeOH (20 mL) was added TEA (0.258 g, 2.56 mmol) at room temperature. The resulting mixture was heated at 80° C. for 12 hours. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by column chromatography (CH2Cl2/MeOH=20:1) and then re-crystallized from MeOH (15 mL) to give the title compound (Example 134, 32.6 mg, 4.4%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.39-7.37 (m, 1H), 7.25 (s, 1H), 7.24-7.14 (m, 1H), 6.09 (s, 1H), 4.73 (s, 2H), 4.33 (s, 2H), 4.09-4.07 (q, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 1.43-1.40 (t, 3H); MS 313.0 [M+1].
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([O:11][C:12](=O)[O:13]C(C)(C)C)([CH3:10])([CH3:9])[CH3:8].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[C:7]([O:11][C:12]([NH:6][CH2:5][CH2:4][CH2:3][Cl:2])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCl
Temperature: 0 °C

Procedure:
The compound of the title, employed as the starting material in example 1, is prepared by slowly adding a solution of 3-chloro-propylamine hydrochloride (12.98 g, 0.1 mol) in dioxane/water (100 ml 2/1 v/v) to a vigorously stirred mixture of di-(tert-butyl)carbonate (24 g, 0.11 mol), 1N Na2CO3 (100 ml) and dioxane/water (200 ml, 2/1 v/v) cooled to 0° C. When the addition is over, the reaction mixture is stirred at room temperature for an additional hour, dioxane is removed under vacuum and the aqueous phase is extracted a few times with ethyl acetate.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.[NH:35]1[C:39]([NH2:40])=[N:38][N:37]=[N:36]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:40][C:39]3[NH:38][N:37]=[N:36][N:35]=3)=[O:31])=[CH:32][CH:33]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc2c(c1)nc(N(Cc1ccc(C(=O)O)cc1)C1CCC(C(C)(C)C)CC1)n2C
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)nc(N(Cc1ccc(C(=O)Nc3nnn[nH]3)cc1)C1CCC(C(C)(C)C)CC1)n2C
Temperature: 40 °C

Procedure:
To a solution of the title compound of Example 14 Step D (0.1 mmol, 45 mg), 1H-tetraazol-5-amine monohydrate (0.2 mmol, 21 mg), HOBt (0.2 mmol, 31 mg) and DIEA (0.3 mmol, 52 μL) in 1 mL of DMF was added EDC (0.2 mmol, 38 mg). The reaction was heated to 40° C. for 3 h, then concentrated under reduced pressure. The residue was taken up in ca. 2:1 dioxane/H2O and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized affording a white solid. 1H NMR (500 MHz, d6-DMSO): δ 12.35 (s, 1H), 8.02 (d, 2H), 7.50-7.56 (overlapping m, 3H), 7.00 (d, 1H), 6.96 (m, 1H), 4.81 (s, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.65 (m, 1H), 2.02 (m, 2H), 1.83 (m, 2H), 1.71 (m, 2H), 1.17 (m, 2H), 1.04 (m, 1H), 0.85 (s, 9H). MS (ESI): m/z 517 (M+H). HPLC A: 2.03 min.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].N[CH2:9][C@@H:10]1CC[CH2:12][N:11]1CC.C(=O)C>>[CH3:12][NH:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4]
Reactant: OC[C@@H]1CCCN1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1CCC[C@H]1CO

Procedure:
By using L-prolinol (500 mg) as a starting material, the title compound (0.22 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:23]2[C:24]([F:29])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=2[Cl:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@@H](O)c2ccccc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](Oc2c(F)ccc(F)c2Cl)c2ccccc2)C1
Yield: 91.5 %

Procedure:
A mixture of (R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 g, 36.1 mmol), 2-chloro-3,6-difluorophenol (8.9 g, 54.1 mmol) and PPh3 (9.93 g, 37.8 mmol) in THF (20.5 mL, 252 mmol) was sonicated for several minutes. While sonicating, DIAD (7.5 mL, 37.8 mmol) was slowly added dropwise to the mixture over several minutes and sonicated further for 15 minutes. The mixture was concentrated and then triturated in excess hexanes for 16 hours. The PPh3 oxide precipitate was filtered off and the organic layer was concentrated to yield a yellow oil. The crude mixture was diluted in EtOAc (300 mL), washed with 1N NaOH (2×200 mL) and saturated aqueous NaCl (100 mL). The organic layer was dried with anhydrous MgSO4, filtered, and concentrated. The organic material was purified by silica gel chromatography (330 g column, 20-50% EtOAc in hexanes) to yield 14 g of (R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a yellow oil which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15]C(=O)OC(C)(C)C)[CH:5]=[N:4][C:3]=1[C:23]#[N:24].[N:25]1[S:26][C:27]([NH2:34])=[C:28]2[CH:33]=[CH:32][CH:31]=[N:30][C:29]=12.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>O1CCOCC1.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]>[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:6]1[N:7]=[C:2]([NH:34][C:27]2[S:26][N:25]=[C:29]3[C:28]=2[CH:33]=[CH:32][CH:31]=[N:30]3)[C:3]([C:23]#[N:24])=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Reactant: Nc1snc2ncccc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1snc2ncccc12
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (53 mg, 0.150 mmol), isothiazolo[3,4-b]pyridin-3-amine (29 mg, 0.0.192 mmol), Cs2CO3 (100 mg, 0.304 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (12 mg, 0.030 mmol) and Pd2 dba3 (15 mg, 0.016 mmol) in dioxane (1 mL) was degassed with Ar, then was stirred at 110 C for 2 h. The mixture was concentrated in vacuo. The residue was dissolved in TFA (4 mL). After 20 min of stirring, excess of TFA was removed in vacuo. The residue was purified by HPLC to give 5-((1R,2S)-2-aminocyclohexylamino)-3-(isothiazolo[3,4-b]pyridin-3-ylamino)pyrazine-2-carbonitrile (36 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:14][CH2:15][CH:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:17]=1)=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:14][CH:15]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:17]=1)=[C:5]2[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)CC1COC(c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)=N1
Agent: O=[Mn]=O
Product: CC(C)Cc1coc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)n1
Temperature: 125 °C
Yield: 21.1 %

Procedure:
A mixture of 6-chloro-3-(4-isobutyl-4,5-dihydro-oxazol-2-yl)-4-phenyl-1H-quinolin-2-one (c) (10.0 mg, 0.025 mmol), MnO2 (15 mg) and CHCI3 (1.0 mL) in a sealed tube was heated at 125° C. for 45 min in a microwave reactor (Smith Synthesizer). The mixture was then filtered through a small pad of celite and purified by prep TLC (5% MeOH/EtOAc) to afford 6-chloro-3-(4-isobutyl-oxazol-2-yl)-4-phenyl-1H-quinolin-2-one (d) (2 mg, 20%). 1H NMR (acetone-d6): δ 11.20 (b s, 1 H), 7.60-7.20 (m, 9 H), 2.20 (d, 2 H), 1.80-1.65 (m, 1 H), 0.75 (d, 6 H). LCMS: 379.3 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: C1COCCN1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(N2CCOCC2)n1

Procedure:
5 g (0.0265 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 4.62 ml (0.053 mol) of morpholine were placed in a fully equipped round-bottomed flask.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl>[Cl-].C[N+](C)(C)CC1C=CC=CC=1>[CH3:7][Si:8]([CH3:11])([CH3:10])[O:1][CH2:2][CH:3]([O:4][Si:8]([CH3:11])([CH3:10])[CH3:7])[CH2:5][O:6][Si:8]([CH3:11])([CH3:10])[CH3:7]
Reactant: OCC(O)CO
Reactant: C[Si](C)(C)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: C[Si](C)(C)OCC(CO[Si](C)(C)C)O[Si](C)(C)C

Procedure:
1 mole of glycerol, 4 moles of trimethylchlorosilane and 0.003 moles of trimethylbenzyl ammonium chloride were reacted at the reflux temperature (54°-102° C.) as in Example 1. Excess silylating agent was distilled off after termination of the reaction. The catalyst was filtered off when the reaction mixture was cold.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:32][CH3:33])(=[O:31])[CH2:25][CH2:26][CH2:27][C:28]([O-])=[O:29]>>[C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:29])[CH2:27][CH2:26][CH2:25][C:24]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CCCC(=O)[O-]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and mono-methyl glutarate to yield (3aR,4S,7aR)-1-(methoxycarbonyl)-4-(m-tolylethynyl)octahydro-1H-indol-4-yl methyl glutarate. MS [M+H]=296 (ester elimination ion); RT=1.26 min; UPLC Method I