Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([CH:14]3[CH2:16][CH2:15]3)[O:12][CH3:13])[O:10][C:6]=2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:26]1[CH2:30]CCC1.[OH2:31]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:14]1([CH:11]([O:12][CH3:13])[C:9]2[O:10][C:6]3[C:7](=[C:2]([C:30]([OH:26])=[O:31])[CH:3]=[CH:4][C:5]=3[O:17][CH3:18])[CH:8]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(Br)c2cc(C(OC)C3CC3)oc12
Reactant: O
Reactant: C1CCOC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)O)c2cc(C(OC)C3CC3)oc12

Procedure:
Prepared from 4-bromo-2-(cyclopropyl-methoxy-methyl)-7-methoxy-benzofuran (350 mg), palladium acetate (25 mg), 1,3-(diphenylphosphino)propane (93 mg) and triethylamine (1.6 ml) in tetrahydrofuran/water (20 ml/10 ml). The title compound was obtained as a cream solid (250 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[Br-].[CH3:15][C:16](=O)[CH2:17]C>>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])[CH:16]=[CH2:15]
Reactant: CCC(C)=O
Reactant: CON(C)C(=O)c1cccc(O)c1
Agent: [Br-]
Product: C=CCOc1cccc(C(=O)N(C)OC)c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 10.8 g (59.6 mmol) B5 and 5.42 ml (71.5 mmol) allylic bromide in 300 ml 2-butanone 41.1 g (298 mmol) potassium carbonate were added. After stirring at 60° C. for 15 hours the solvent was distilled off and the residue partitionated between ethyl acetate and water. The organic layer was dried over sodium sulfate and the solvent removed in vacuo. Yield: 12.1 g (92%) B10 as a yellowish oil which was used without further purification.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH2:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=2)[CH2:9]1)[CH3:7]>>[CH2:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=2)[CH2:9]1)[CH3:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCN1Cc2ccc(NC(C)=O)cc2C1
Agent: [K+]
Product: CCN1Cc2cc(NC(C)=O)c([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49.8 %

Procedure:
KNO3 (1.33 g, 13.2 mmol) was added in small portions, over 10 min, to a stirred solution of acetamide 246 (2.45 g, 12.0 mmol) in CH2SO4 (50 mL) at 0° C. and the reaction mixture was stirred at 0° C. for a further 45 min. The mixture was poured onto ice, made basic with cNH3 and extracted with DCM (3×100 mL). The solvent was evaporated to give a brown oil which was purified by chromatography on neutral Al2O3, eluting with a gradient (0-20%) of EtOAc/pet. ether, to give nitroacetamide 247 (1.49 g, 50%) as a yellow solid: mp EtOAc/pet. ether) 85-87° C.; 1H NMR δ 10.43 (br s, 1H, NH), 8.62 (s, 1H, H-7), 8.03 (s, 1H, H-4), 3.96 (s, 2H, CH2N), 3.92 (s, 2H, CH2N), 2.79 (q, J=7.2 Hz, 2H, CH2N), 2.28 (s, 3H, COCH3), 1.21 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C12H16N3O3 (MH+) m/z 250.1192, found 250.1195. Anal. calcd for C12H15N3O3: C, 57.8; H, 6.0; N, 16.9. Found: C, 57.9; H, 5.9; N, 16.7%.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([N:9]1[CH:15]([CH2:16][CH2:17][CH2:18][N:19](C)[CH3:20])[C:14]2[CH:22]=[CH:23][CH:24]=[C:25]3[CH2:26][CH2:27][N:12]([C:13]=23)[C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]1=2)(=[O:8])[CH3:7].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1C=CC=CC=1.O.ClCCl>[CH2:36]([O:35][C:33](=[O:34])[N:19]([CH2:18][CH2:17][CH2:16][CH:15]1[C:14]2[CH:22]=[CH:23][CH:24]=[C:25]3[CH2:26][CH2:27][N:12]([C:13]=23)[C:11]2[CH:28]=[CH:29][CH:30]=[CH:31][C:10]=2[N:9]1[C:6](=[O:8])[CH3:7])[CH3:20])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)N1c2ccccc2N2CCc3cccc(c32)C1CCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)N(C)CCCC1c2cccc3c2N(CC3)c2ccccc2N1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 27.64 g of powdered anhydrous sodium bicarbonate in 415 ml of benzene containing 23.0 g of 7-acetyl-N,N-dimethyl-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine-6-propanamine was treated with 19.0 ml of ethyl chloroformate. After an overnight reflux under nitrogen, 6.3 ml more of ethyl chloroformate was added, and reflux continued another 2 hours. TLC still showed the presence of the starting material at this point, and a further addition of 6.3 ml of ethyl chloroformate was made. After 2 hours another 12.6 ml of ethyl chloroformate was added, reflux continued for another 1.5 hours, and the mixture cooled to room temperature. The reaction mixture was diluted with 500 ml of distilled water, stirred for a while, and poured into a separatory funnel, and the phases were separated. The aqueous phase was extracted with 250 ml of ethyl acetate. The combined organic phases were extracted with 200 ml of 2N hydrochloric acid, washed with 200 ml of water and 200 ml of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a gum weighing 24.37 g. This material was dissolved in 150 ml of dichloromethane, the resulting solution was divided into two halves, and each half was purified by flash chromatography on 500 g of silica gel, using dichloromethane and then 1% methanol/dichloromethane as solvent. The purest fractions were combined and concentrated in vacuo to a foam which partially crystallized upon standing. Trituration with hexane fully solidified this material, which was filtered, washed with hexane and dried in vacuo to afford 11.65 g of solid, m.p. 125°-128° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([CH2:10][NH:11][CH3:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:20][C:19]=2[CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([CH2:10][N:11]([CH3:12])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:21]3[CH:22]=[N:23][C:24]4[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=4[CH:20]=3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CNCc1sc2ccc(F)cc2c1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of (5-fluoro-3-methylbenzo[b]thiophen-2-yl)-N-methylmethanamine (168 mg, 0.8 mmol) in DMF (5 mL) were added in sequential order (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (159 mg, 0.73 mmol), 1-hydroxybenzotriazole (111 mg, 0.8 mmol), diisopropylethylamine (381 uL, 2.19 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (160 mg, 0.8 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield the title compound as a pale brown solid (224 mg, 75%): 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.37 (s, 1H), 8.08 (s, 1H), 7.76-8.00 (m, 1H), 7.39-7.63 (m, 2H), 7.02-7.33 (m, 2H), 4.87-5.11 (rotamers, 2s, 2H), 3.16 (s, 3H), 2.56-2.89 (m, 2H), 2.49-2.51 (m, 2H), 2.39 (s, 3H); MS (ESI) m/e 410 (C22H20FN3O2S+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14](Cl)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.Cl.[F:21][C:22]1([F:26])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14]([N:24]3[CH2:25][C:22]([F:26])([F:21])[CH2:23]3)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1
Reactant: FC1(F)CNC1
Reactant: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 93.5 %

Procedure:
6-Chloro-7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (1.00 g, 3.14 mmol) obtained in step 3 was dissolved in acetonitrile (10 mL), and the solution was stirred at room temperature for 1.25 hours after adding 3,3-difluoroazetidinehydrochloride (611 mg, 4.71 mmol) and triethylamine (1.31 mL, 9.43 mmol). A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture. The precipitated crystals were collected by filteration, and washed with water. The resulting crude product was purified by silica gel column chromatography (heptane/ethyl acetate=80/20→50/50) to give 6-chloro-3-(3,3-difluoroazetidin-1-ylsulfonyl)-2-isopropylimidazo[1,2-a]pyridine-7-carbonitrile (1.10 g, yield 93%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N+:58]([O-:60])=[O:59])[C:47]1=[O:61])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:63])([CH3:62])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N+:58]([O-:60])=[O:59])[C:47]1=[O:61])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2[N+](=O)[O-])C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2[N+](=O)[O-])C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
A solution containing the product from Example 2C (0.082 g, 0.154 mmol) in THF (1.5 mL) was treated with the product from Example 123A (0.057 g, 0.17 mmol), DEPBT (0.069 g, 0.231 mmol), and N,N-diisopropylethylamine (0.135 mL, 0.77 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate to give the title compound (0.080 g, 61% yield).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:30])([CH3:29])[CH:21]([C:23]1[O:24][C:25]([CH3:28])=[N:26][N:27]=1)[NH2:22]>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:22][CH:21]([C:23]3[O:24][C:25]([CH3:28])=[N:26][N:27]=3)[C:20]([CH3:19])([CH3:29])[CH3:30])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: Cc1nnc(C(N)C(C)(C)C)o1
Product: Cc1nnc(C(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(C)(C)C)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2,2-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)propan-1-amine (example 174b) as starting materials and isolated (128 mg, 81%); MS (ESI, m/z): 413.6 (M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([Cu])#[N:21].CN(C)C=O.C(N)CN>O>[C:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]2=[O:11])=[CH:4][CH:3]=1)#[N:21]
Reactant: N#C[Cu]
Reactant: CCCCCCCCC1Cc2ccc(Br)cc2C1=O
Solvent: O
Solvent: NCCN
Solvent: CN(C)C=O
Product: CCCCCCCCC1Cc2ccc(C#N)cc2C1=O
Temperature: 160 °C
Reaction time: 6 h
Yield: 55.7 %

Procedure:
Subsequently, 150 g (4.7×10-1M) of 6-bromo-2-octyl-1-indanone, 62.3 g (7.0×10-1M) of CuCN and 800 ml of dimethylformamide (DMF) were placed in a 2 liter-reaction vessel, followed by stirring for 6 hours at 160° C. After the reaction, the reaction mixture was cooled and poured into 3 liter of water and 100 ml of ethylenediamine was added, followed by extraction with ethyl acetate. The organic layer was washed with water, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/chloroform=1/1) to obtain 69.6 g of 6-cyano-2-octyl-1-indanone (Yield: 55%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:22]([NH:26][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
In a 100 ml round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.00 g, 2.69 mmol) was dissolved in DMF (6 ml). tert-Butylamine (1.7 ml, 16.2 mmol) was added followed by HATU (1.12 g, 2.95 mmol). The yellow suspension was stirred at room temperature for 72 h then quenched with water and extracted with a mixture of diethyl ether and EtOAc. The organic layers were washed twice with water and once with brine then combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 989 mg (86%) of 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.40 (s, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 5.65 (s, 2H), 3.46-3.58 (m, 2H), 1.54 (s, 9H), 0.84-0.98 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.[CH3:20][N:21]([CH3:39])[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34](OCC)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O1CCCCC1.O1CCCC1>[CH3:20][N:21]([CH3:39])[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1
Reactant: CCOC(=O)c1cnc2cc(OCCN(C)C)ccn12
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Solvent: C1CCOC1
Solvent: C1CCOCC1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN(C)C)ccn45)cccc32)n1
Temperature: 0 °C
Yield: 51.7 %

Procedure:
3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (59 mg, 0.24 mmol) was dissolved in tetrahydropyran (DriSolve; 1.2 mL) and degassed before back-filling with nitrogen. The solution was cooled in an ice water bath for 15 minutes before dropwise addition of lithium bis(trimethylsilyl)amide (0.25 mL, 1 M in tetrahydrofuran). The reaction stirred for 10 minutes before dropwise addition into a solution of ethyl 7-(2-(dimethylamino)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (31 mg, 0.12 mmol) in tetrahydrofuran (DriSolve; 1.2 mL) cooled in an ice-water bath. The reaction was then stirred while being cooled in the ice-water bath for 1.5 hours. The reaction was quenched with water and concentrated. Purification using reverse phase chromatography, eluting with a gradient from 10% to 60% ACN/water, gave 7-(2-(dimethylamino)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (30 mg). MS m/z 484.1 (M+1, APCI+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.[Li]C(C)(C)C.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16]>O1CCCC1>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:5]1[S:1][C:2]2[CH:8]=[C:7]([Sn:15]([CH3:17])([CH3:16])[CH3:14])[S:6][C:3]=2[CH:4]=1
Reactant: c1cc2sccc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2sc([Sn](C)(C)C)cc2s1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In a 3-neck round bottom flask equipped with an argon inlet and an addition funnel, thieno[3,2-b]thiophene (7.5 g, 54 mmol) was dissolved in tetrahydrofuran (1 L). After the solution was cooled to −78° C. using an isopropanol/dry ice bath, t-BuLi (100 mL, 170 mmol) was transferred by cannula to the addition funnel. The organolithium reagent was then added dropwise. After completion of the addition, the mixture was stirred for 20 min at −78° C. then warmed up with an isopropanol bath at room temperature for 30 minutes during which a yellow precipitate formed. The solution was cooled back at −78° C., and after cannula transfer to the addition funnel, trimethyltin chloride (200 mL of 1 M solution in THF, 200 mmol) was added dropwise. During addition of trimethyltin chloride, the precipitate disappeared and the solution turned light brown. After warming to room temperature the solution was stirred for 30 minutes then was poured into ice-cold water. The aqueous phase was further extracted with hexane. The combined organic phases were washed with cold water then dried with magnesium sulfate. After filtration, the solvent is evaporated under vacuum to yield a grey-brown solid. The product was purified by precipitation of a chloroform solution into methanol followed by filtration (13.2 g, 53%). Spectral data: 1H NMR (CDCl3, 300 MHz): δH 0.41 (s, 18H), 7.26 (s, 2H). 13C (CDCl3, 75 MHz): δ 7.99, 126.29, 141.4, 147.62.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=O)[N:17](C)[CH:18]=2)=[CH:4][N:3]=1.[Cl:21]C1N=CC(C(=CN(C)C)C(C2OC=CC=2)=O)=CC=1.NC(N)=N>>[Cl:21][C:16]1[N:17]=[CH:18][C:13]([C:5]2[C:6]([C:8]3[O:9][CH:10]=[CH:11][CH:12]=3)=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: CN(C)C=C(C(=O)c1ccco1)c1ccc(Cl)nc1
Reactant: Cn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Agent: N=C(N)N
Product: Nc1ncc(-c2ccc(Cl)nc2)c(-c2ccco2)n1

Procedure:
The process for preparing 5-[2-amino-4-(2-furyl)pyrimidin-5-yl]-1-methylpyridin-2(1H)-one disclosed in patent document 1 is, as shown in the reaction scheme below, a method of allowing 2-(6-chloro-3-pyridyl)-3-dimethylamino-1-(2-furyl)-2-propene-1-one to react with guanidine to afford 5-(6-chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinylamine, oxidizing this to afford 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone, and then methylating this.
Reaction SMILES: [CH:1]1C(CCCC(O)=O)=CC=C(N(CCCl)CCCl)C=1.[CH3:20][C:21]([C@H:23]1[CH:27]2[CH:28]3[C@@:41]([CH3:44])([CH2:42][CH2:43][C@@:26]2([C:65]([OH:67])=[O:66])[CH2:25][CH2:24]1)[C@@:40]1([CH3:45])[CH:31]([C@:32]2([CH3:64])[CH:37]([CH2:38][CH2:39]1)[C:36]([CH3:47])([CH3:46])[C@@H:35]([O:48][C:49]([CH2:51][N:52]([O:62][CH3:63])[C@@H:53]1[O:58][CH2:57][C@@H:56]([OH:59])[C@H:55]([OH:60])[C@H:54]1[OH:61])=[O:50])[CH2:34][CH2:33]2)[CH2:30][CH2:29]3)=[CH2:22]>>[CH3:1][C@H:57]1[O:58][CH:53]([N:52]([O:62][CH3:63])[CH2:51][C:49]([O:48][C@@H:35]2[C:36]([CH3:46])([CH3:47])[CH:37]3[C@@:32]([CH3:64])([CH:31]4[C@@:40]([CH3:45])([CH2:39][CH2:38]3)[C@@:41]3([CH3:44])[CH:28]([CH:27]5[C@@:26]([C:65]([OH:67])=[O:66])([CH2:43][CH2:42]3)[CH2:25][CH2:24][C@H:23]5[C:21]([CH3:20])=[CH2:22])[CH2:29][CH2:30]4)[CH2:33][CH2:34]2)=[O:50])[C@H:54]([OH:61])[C@@H:55]([OH:60])[C@H:56]1[OH:59]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CCC4[C@@]5(C)CC[C@H](OC(=O)CN(OC)[C@@H]6OC[C@@H](O)[C@H](O)[C@H]6O)C(C)(C)C5CC[C@]43C)C12
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CCC4[C@@]5(C)CC[C@H](OC(=O)CN(OC)C6O[C@H](C)[C@H](O)[C@H](O)[C@H]6O)C(C)(C)C5CC[C@]43C)C12

Procedure:
A conformational study of sugar acetylhydrazides by Bendiak indicated that natural hexose and pentose (e.g., D-Glc, D-Gal, D-Xyl, etc.) analogs formed pyranosides, as evidenced by 1H NMR. Similar findings were reported for mono- and oligosaccharide chemoselective ligations with biotinyl, long-chain acyl, peptidyl, and adipyl hydrazides. In contrast, the current chlorambucil study revealed a trend that mirrored that which was observed for the 66-70 subset. Specifically, D-fucoside 72 was formed only as the cyclic compound (67% yield), D-glucuronolactonide 73 and D-xyloside 75 were a mixture of the open and closed conformers (46% and 47%, respectively), and D-threoside 74 adopted the open-chain imine (86%). These results indicate that closure of the glycoside may not only be dependent on the type of sugar but possibly the nature of the aglycon as well. It was also notable that only the β-anomer of the closed-rings was observed while the hydrazyl imines were isolated as mixtures of E- and Z-isomers (FIG. 7).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[N:20]=[C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][C:24]=1[C:41]([F:44])([F:43])[F:42])[NH2:22].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:18][N:22]=[C:21]([C:23]4[CH:40]=[CH:39][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:31]5)=[CH:25][C:24]=4[C:41]([F:44])([F:42])[F:43])[N:20]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)c(C(F)(F)F)c2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
A mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (0.030 g, 0.104 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.039 g, 0.104 mmol), BOP-Cl (0.035 g, 0.136 mmol), and triethylamine (0.044 mL, 0.313 mmol) in N,N-dimethylformamide (1 mL) was shaken on platform shaker at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography using a mixture of 20% mixture of ethyl acetate in hexane to give tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.010 g, 0.017 mmol, 16% yield) as a white solid. The compound had an HPLC ret. time=3.16 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=595.2.