Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[NH2:13].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=[C:7]2[NH2:13]
Reactant: Nc1nc(Cl)nc2c(Br)cccc12
Reactant: CC(C)(C)N
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(N)c2cccc(Br)c2n1
Temperature: 120 °C
Yield: 106.9 %

Procedure:
A microwave vial was charged with 8-bromo-2-chloroquinazolin-4-amine (484a; 0.109 g, 0.422 mmol) and tert-butylamine (Aldrich; 1.33 mL, 12.65 mmol). The slurry was heated to 120° C. in a biotage initiator microwave for 30 min. 0.5 mL NMP was added to give a solution and the reaction was heated to 120° C. in a biotage initiator microwave for 30 min. The reaction was heated to 150° C. in a biotage initiator microwave for 30 min. The reaction was heated to 160° C. in a biotage initiator microwave for 30 min and then was heated to 170° C. in a biotage initiator microwave for 30 min. The reaction was partitioned between water and EtOAc. The organic layer was washed with water 2 times, saturated aqueous NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-N2-(tert-butyl)quinazoline-2,4-diamine (0.133 g, 0.451 mmol, quant. yield) as a brown foam: 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (1H, dd, J=7.5, 1.3 Hz), 7.48 (1H, d, J=7.8 Hz), 6.92 (1H, t, J=7.8 Hz), 5.27 (2H, br. s.), 5.02 (1H, br. s.), 1.55 (9H, s). m/z (ESI, +ve ion) 295.0/297.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:21]=[O:22]>O1CCCC1>[CH2:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[O:22])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CN(C)C=O
Reactant: CCCCOCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOCc1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.92 h
Yield: 81.3 %

Procedure:
To a solution of 1-bromo-4-butoxymethyl-benzene (11.5 g, 47.3 mmol) described in Manufacturing Example 4-1-1 in tetrahydrofuran (200 mL) was added n-butyl lithium (32.5 mL, 1.6 M hexane solution, 52.0 mmol) at −78° C. This mixture was stirred for 55 minutes at −78° C., and N,N-dimethylformamide (4.4 mL, 56.8 mmol) was added thereto at −78° C. This mixture was warmed to room temperature, and stirred for 20 minutes. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (7.39 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]#[CH:20]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][C:18]#[C:19][CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
N-tert-butoxycarbonyl L-serine 12 (25.42 g, 0.1239 mol) was dissolved in DMF (190 mL) and the solution cooled to 0° C. (ice bath). Sodium hydride (60% (w/w) dispersion in mineral oil, 10.90 g, 0.2725 mol) was added over 15 min and the reaction mixture stirred for 1 h at 0° C. 3-Bromopropyne (80% (w/w) solution in toluene, 20.25 g, 0.1362 mol) was added dropwise over 15 min. The reaction mixture was stirred for 1 h at 0° C., after which the ice bath was removed and stirring continued for 3 h 40 min at room temperature. The solvent was evaporated and the residue dissolved in H2O (800 mL). The solution was washed with Et2O (3×350 mL) and acidified to pH 2 by addition of 3 M HCl. The resulting mixture was extracted with EtOAc (5×350 mL). The combined organic extracts were dried with anhydrous MgSO4 and the solvent evaporated affording a yellow/orange viscous oil (30.51 g). A portion of the oil (8.70 g) was purified by flash column chromatography (eluent: EtOAc/hexane/AcOH (23:27:1)). The fractions containing reasonably pure compound by TLC (total volume: 950 mL) were washed with 0.5 M HCl (3×500 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a pale yellow, viscous oil (6.58 g, corresponds to 23.03 g from the given amounts of starting materials, 77%), with spectral characteristics in accordance with literature data10; 1H NMR (200 MHz, DMSO-d6) δ 12.62 (br s, 1H, COOH), 6.88 (d, J=8.2 Hz, 1H, NH (rotomer 1)), 6.53 (d, J=6.4 Hz, 1H, NH (rotomer 2)), 4.21-4.06 (m, 1H, CαH), 4.13 (d, J=2.4 Hz, 2H, CH2CCH), 3.66 (d, J=5.4 Hz, 2H, CH2), 3.40 (t, J=2.4 Hz, 1H, CCH), 1.38 (s, 9H, (CH3)3); 13C NMR (75 MHz, DMSO-d6) δ 171.8, 155.4, 79.9, 78.3, 77.4, 68.8, 57.7, 53.6, 28.2; HRMS (m/z): [M+Na]+ calcd. for C11H17NO5Na, 266.1004. found, 266.1010; Anal. Calcd. for C11H17NO5: C, 54.31; H, 7.04; N, 5.76. Found: C, 54.7; H, 7.1; N, 5.5.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.O>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/CCC#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/CCC#Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 91.2 %

Procedure:
To a solution of ethyl 7-phenylhept-2E-en-6-ynoate (2.5 g) in methanol was added KOH (2.6 g) in water (6 ml). The mixture was stirred at 50° C. under a nitrogen atmosphere for 40 minutes, cooled, diluted with water (20 ml) and washed with ether (15 ml). The aqueous layer was acidified with 10% HCl and extracted with ether. The ether extracts were combined and dried over MgSO4, and the solvent was distilled off (adding dry benzene (4 ml) to form azetrope with traces of water) to give 7-phenylhept-2E-en-6-ynoic acid (2 g) as a colourless oily solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH2:12]=O>C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Brc1ccc2c(c1)CNCC2
Solvent: O=CO
Product: CN1CCc2ccc(Br)cc2C1
Temperature: 150 °C
Yield: 75.3 %

Procedure:
To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (1 g, 4.7 mmol) in formic acid (20 mL) was added formalin (1.2 mL, 15 mmol). The solution was heated to 150° C. for 5 min under microwave irradiation. The solvent was removed in vacuo and the residue was dissolved into ethyl acetate (100 mL), washed with sat. sodium bicarbonate (2×10 mL), brine (10 mL) and dried over MgSO4. Removal of the solvent gave the title compound as a white solid (800 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.3 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 4.11 (s, 2H), 3.37-3.34 (m, 2H), 3.27-3.24 (m, 2H) 2.95 (s, 3H); MS ESI 225.9, 227.9 [M+H]+, calcd for [C10H12BrN+H]+226.0, 228.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][O:7][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CO)cc(OC)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A mixture of 3,5-dimethoxybenzyl alcohol (4.0 g), t-butyl-diphenylsilyl chloride (6.54 g) and imidazole (3.28 g) in DMF (60 mL) was stirred at room temperature for 24 h. DMF was evaporated and the residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 20%) to yield 8.5 g of 3,5-dimethoxy-1-[(t-butyldiphenylsilyloxy)methyl]benzene. ESMS: m/z 407 (MH+).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[Cl:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=1C(O)C>C(Cl)Cl>[C:5]([O:4][CH:1]([C:16]1[C:17]([Cl:22])=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[Cl:14])[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
Acetic anhydride (1.42 mL, 15 mmol) and pyridine (1.7 mL, 21 mmol) were added sequentially to a solution of compound A1 (2.2 g, 10.5 mmol) in 20 mL of CH2Cl2. The reaction mixture was stirred at room temperature for 12 h and then evaporated to give a yellowish oil residue. The residue was purified by flash chromatography (eluting with 7→9% EtOAc in hexanes) to give compound A2 as a colorless oil (2.26 g; 9.0 mmol; 85.6% yield); 1H NMR (400 MHz, chloroform-D) δ ppm 1.88 (d, J=6.82 Hz, 3H) 2.31 (s, 3H) 6.62 (q, J=6.82 Hz, 1H) 7.25 (t, J=8.46 Hz, 1H) 7.49 (dd, J=8.84, 5.05 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH2:8][Br:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nc(CBr)ccc1Br
Temperature: 90 °C
Reaction time: 1 h

Procedure:
In 21 mL of carbon tetrachloride, 3-bromo-2-chloro-6-methylpyridine (880 mg, 4.26 mmol) was dissolved, and N-bromosuccinimide (682 mg, 3.83 mmol) and AIBN (70 mg, 0.426 mmol) were added, followed by stirring at 90° C. for one hour. The resulting reaction solution was concentrated, and the residue thus obtained was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5), whereby 3-bromo-6-(bromomethyl)-2-chloropyridine was obtained as a crude purified product.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>O1CCCC1.[OH-].[Na+]>[C:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of phenyl-[1-(2-phenylethyl)-4-piperidyl]-ketone (0.10 g) in tetrahydrofuran (0.40 g) was added to wet surface-modified adsorbent of Example 10 (1.0 g) in excess aqueous NaOH pH 9.0 (2.0 mL). This mixture was stirred at ambient temperature for 30 minutes. After this, NaBH4 (20 mg) was added and the resulting mixture was stirred at ambient temperature for 16 hours. The liquid phase was then decanted and the adsorbent was washed with tetrahydrofuran in order to quantitatively extract all product from the resin. The tetrahydrofuran washings were combined with liquid phase and analyzed by chiral High Pressure Liquid Chromatography (HPLC) using a Chiracel OD-R column commercially available from Chiral Technologist Incorporation and 1.0 M aqueous NaClO4 /acetonitrile (60/40 by volume) as a mobile phase. The product α-phenyl-[1-(2-phenylethyl)]-4-piperidinemethanol of a moderate enantiomeric purity (enantiomeric excess of S (-)=25 percent) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]([OH:22])[CH3:21].C(Cl)Cl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:12][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH:20]([OH:22])[CH3:21])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(O)c1ccncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(O)c1ccncc1-c1ccc(C#N)c(F)c1
Temperature: 100 °C
Yield: 52.3 %

Procedure:
To the solution of 4-cyano-3-fluoro phenylboronic acid (247 mg, 1.50 mmol), 1-(3-Bromo-pyridin-4-yl)-ethanol (303 mg, 1.50 mmol) and PdCl2(dppf). CH2Cl2 adduct (98 mg, 0.12 mmol) in DMF (6 mL) was added 2M Na2CO3aq (1.50 ml, 3.00 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (10% MeOH/DCM=0-25%) to give 2-Fluoro-4-[4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (190 mg, 52%) as colorless solid; ESI-MS m/z: 243 [M+1]+, Retention time 1.05 min
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: NN
Reactant: COc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1OC
Yield: 80.3 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (200 mg, 0.48 mmol, prepared in Synthetic Example 22) in DMF (5 ml) was added hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(3,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (159 mg, 80%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][CH:56]3[CH2:58][CH2:57]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([Cl:54])[CH:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[C:68]([CH2:70][C:71](O)=[O:72])#[N:69]>C(Cl)Cl>[Cl:54][C:50]1[CH:49]=[C:48]([NH:47][C:45]([C:42]2[N:40]3[N:41]=[C:36]([NH:35][C@H:32]4[CH2:31][CH2:30][C@H:29]([NH:28][C:71](=[O:72])[CH2:70][C:68]#[N:69])[CH2:34][CH2:33]4)[CH:37]=[C:38]([NH:55][CH:56]4[CH2:57][CH2:58]4)[C:39]3=[N:44][CH:43]=2)=[O:46])[CH:53]=[CH:52][N:51]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Reactant: N#CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (60.2 mg, 0.136 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (20.00 mg, 0.045 mmol), DIEA (0.032 mL, 0.181 mmol) and 2-cyanoacetic acid (7.72 mg, 0.091 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 min, concentrated and diluted with MeOH and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to isolate N-(2-chloropyridin-4-yl)-6-((trans)-4-(2-cyanoacetamido)cyclohexylamino)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (11 mg, 0.022 mmol, 47.7% yield) as white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.772 minutes. [M+H]=508.11. 1H NMR (400 MHz, MeOD) δ ppm 8.24-8.39 (1H, m), 7.95-8.03 (1H, m), 7.87-7.97 (1H, m), 7.51-7.67 (1H, m), 5.98-6.11 (1H, m), 3.60-3.83 (2H, m), 2.47-2.66 (1H, m), 2.19-2.37 (2H, m), 1.96-2.19 (2H, m), 1.28-1.55 (4H, m), 0.77-0.96 (2H, m), 0.52-0.75 (2H, m).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C:25]([F:28])([F:29])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[OH:16])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccccc3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A mixture of 2-(5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-1-phenylethanone (6.0 mg, 15.0 μmol) and NaBH4 (1.7 mg, 45.0 μmol) in methanol (250 μL) was stirred at the room temperature for 1 h. The reaction mixture was directly purified by preparative HPLC (column: Gemini 5 um C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 72:25% to 5:95%. WL: 230 nm Flow: 30 mL/min.) to afford the title compound as white solid (2.3 mg, 38%). MS(m/e): 403.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:19]OC(C1CCN(C(OC(C)(C)C)=O)CC1)=O>>[CH3:1][O:2][C:3]([C:5]1([CH2:18][CH3:19])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using the method of 4-methylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester, the title compound is synthesized from piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester and isolated as a tan oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].Cl.[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C@H:14]([NH2:17])[CH2:15][F:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C>[F:1][C:2]([F:7])([F:6])[C:3]([NH:17][C@H:14]([CH2:15][F:16])[CH2:13][CH2:12][C:11]([O:10][CH3:9])=[O:18])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)CC[C@H](N)CF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)CC[C@@H](CF)NC(=O)C(F)(F)F
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
0.28 g of triethylamine and 0.96 ml of trifluoroacetic acid were added to 0.28 g of 4, and the mixture was cooled to -10° C. 0.25 ml of trifluoroacetic anhydride was added drop-by-drop. The resulting mixture was allowed to warm to room temperature and stirred for 90 minutes. Volatile materials were evaporated under reduced pressure, and the residue, an oil, was eluted through a column of florisil, using ethyl acetate as eluent. After evaporation of the solvent, the resulting oil was stripped under reduced pressure to give 8, as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[OH-].[Na+].O>[C:14]1([S:20]([O:1][C:2]2[CH:13]=[CH:12][C:5]3[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=3[CH:3]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1csc2ccc(O)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Yield: 88.5 %

Procedure:
To a solution of 8.63 g (44.4 mol) of 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1) (J. Chem. Soc (C), 1899-1905 (1967), M.Martin-Smith et al.) in 160 ml of 80% aqueous tetrahydrofuran and 44 ml of 1N sodium hydroxide was added 87 ml of 0.56N sodium hydroxide and 6.2 ml (48.4 mmol) of benzenesulfonylchloride simultaneously with keeping at pH 11-12 with stirring under ice-cooling. After the reaction completion, the mixture was diluted with water, alkalized and washed with toluene. The aqueous layer was weakly acidified with conc. hydrochloric acid under stirring. The precipitated crystals were filtered, washed with water, and dried to give 14.33 g of 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (2).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:2]1
Reactant: OCCCC1CCCOC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCC1CCCOC1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To the solution of 3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (10.35 g, 0.0719 mol) in CH2Cl2 (200 mL) was added Dess-Martin periodinane (61.24 g, 0.1438 mol). The mixture was stirred at rt. When the reaction was over, the solution was poured into Et2O (300 mL) and anhydrous K2CO3 (19.84 g, 0.1438 mol) was added. The mixture was filtered. The filtrate was dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give 3-(tetrahydro-2H-pyran-3-yl)propanal (8.25 g, 80%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:17][CH3:18])[CH:8]=1)(=O)=O.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:18][O:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[CH:16][C:7]([C:21]#[N:22])=[CH:8]2
Reactant: COc1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cccc2cc(C#N)ccc12
Temperature: 80 °C
Yield: 90 %

Procedure:
A solution of 5-methoxy-2-naphthyl trifluoromethanesulfonate (1.04 g, 3.4 mmol) in DMF (5 mL) is degassed by repeatedly evacuating the flask then flushing with N2. Zinc cyanide (234 mg, 2.0 mmol) is added followed by Pd(PPh3)4 (196 mg, 0.17 mmol). The resulting mixture is again degassed and heated to 80° C. for 3 hours. The reaction is allowed to cool, poured into water and washed twice with toluene and once with CH2Cl2. The combined organic extracts are dried (Na2SO4), filtered and concentrated. The resulting material is purified by column chromatography (step gradient, 25–50% CH2Cl2 in hexanes) to give 5-methoxy-2-naphthonitrile as a white solid (560 mg, 90%). HRMS (EI) calculated for C12H9NO 183.0684, found 183.0684.