Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][C:28]([C:30]6[O:31][C:32]([CH:35]=O)=[CH:33][CH:34]=6)=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:37][CH3:38])=[N:10]2)=[N:3]1.C1COCC1.[CH3:44][NH:45][CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][C:28]([C:30]6[O:31][C:32]([CH2:35][N:45]([CH3:46])[CH3:44])=[CH:33][CH:34]=6)=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:37][CH3:38])=[N:10]2)=[N:3]1
Reactant: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5ccc(C=O)o5)ccn34)c12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5ccc(CN(C)C)o5)ccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)-7-(5-formylfuran-2-yl)imidazo[1,2-a]pyridine-3-carboxamide (36 mg) in 1 mL of a 1:1 DCM:THF mixture was treated at ambient temperature with excess 2.0 M dimethylamine solution in MeOH. The reaction mixture was stirred at ambient temperature for 30 minutes. A large excess of sodium triacetoxyborohydride (10 equivalents) was added, and the reaction stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, dissolved in a small amount of MeOH, and subjected to preparative thin-layer chromatography with a 2% 7N ammonia-MeOH, 8% MeOH in DCM solution as eluent to give the desired product (12.8 mg). MS (ES+APCI) m/z=537 (M+H) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.[OH-].[Na+]>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: COc1ccc(C=CC(=O)O)cc1OC
Temperature: 80 °C

Procedure:
3,4-Dimethoxybenzaldehyde (25 g, 0.15 mol), malonic acid (32.87 g, 0.31 mol) and piperidine (1 mL) were dissolved in pyridine (100 mL) under stirring. The reaction mixture was heated at 80° C. for 3 h, after which the temperature was further increased to 120° C. and maintained at this temperature for 3 h. The reaction mixture was cooled, diluted with water (70 mL) and pH of the solution was adjusted to 9 by addition of 10% aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (3×150 mL). The pH of the aqueous layer was adjusted to 2 by addition of aqueous HCl (1:1) and the resulting solid was filtered and dried to afford the title compound.
Reaction SMILES: [C:1](O[C@@H](C1C(C)=CC2C(=CC=C(OS(C(F)(F)F)(=O)=O)C=2)C=1C1C=CC(Cl)=CC=1)C(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[CH:48]=[C:47]2[C:42]([CH:43]=[C:44]([CH3:63])[C:45]([CH:56]([OH:62])[C:57]([O:59][CH2:60][CH3:61])=[O:58])=[C:46]2[C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)=[CH:41][CH:40]=1>>[C:1]([O:62][CH:56]([C:45]1[C:44]([CH3:63])=[CH:43][C:42]2[C:47](=[CH:48][C:39]([Cl:38])=[CH:40][CH:41]=2)[C:46]=1[C:49]1[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=1)[C:57]([O:59][CH2:60][CH3:61])=[O:58])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1-c1ccc(Cl)cc1

Procedure:
Ethyl 2-tert-butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetate was prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)acetate of Example 51, except using racemic ethyl 2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate. Material was carried on crude without further characterization.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[NH2:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.[OH-].[Na+].[Cl-:19].[K+].[Pt+2:21].[Cl-:22].[Cl-]>O>[Pt+2:21].[Cl:19][C@H:13]1[C@@H:12]([NH2:11])[CH2:16][CH2:15][N:14]1[Cl:22]
Reactant: [Cl-]
Reactant: N[C@H]1CCNC1
Agent: [Pt+2]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [K+]
Solvent: O
Product: N[C@H]1CCN(Cl)[C@H]1Cl
Temperature: 25 °C
Yield: 63.2 %

Procedure:
(3S)-3-Aminopyrrolidine L(+)-tartrate (236 mg) prepared in Reference Example 1-(2) is dissolved in water (40 ml) and thereto is added sodium hydroxide (80 mg), and the mixture is stirred at room temperature. To the solution is added platinum (II) potassium chloride (415 mg), and the mixture is stirred at room temperature overnight. The precipitated solid is removed by filtration, and the filtrate is concentrated to dryness under reduced pressure. To the residue is added water (2 ml), and the resulting crystals are separated by filtration and washed with water and acetone to give cis-dichloro-(3S)-3-aminopyrrolidine platinum (II) (221 mg) as pale yellow crystal.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[C:11](=[O:12])[CH2:10][O:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Sn](CCCC)(CCCC)CCCC.[Cl-].[Li+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[C:11](=[O:12])[CH2:10][O:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C1COC(=O)N1Cc1ccc(Br)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O=C1COC(=O)N1Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, a mixture of 0.59 g (2.18 mmol) of 3-(4-bromobenzyl)-1,3-oxazolidine-2,4-dione, obtained in step 9.1., 1.60 g (4.35 mmol) of pyridin-2-yltri-n-butylstannane, 0.28 g (6.6 mmol) of lithium chloride and 0.125 g (0.10 mmol) of palladium tetrakis(triphenylphosphine) in 15 ml of toluene is heated at reflux overnight. It is cooled to ambient temperature, filtered on paper and rinsed in succession with 10 ml of toluene, 10 ml of ethyl acetate and 10 ml of toluene. The filtrates are concentrated under reduced pressure. The residue is taken up in 50 ml of acetonitrile and washed with four times 25 ml of n-hexane. The acetonitrile phase is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with a 70/30 then 60/40 mixture of cyclohexane and ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: NCCCO
Product: O=[N+]([O-])c1c(NCCCO)cc(Cl)cc1NCCCO
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
0.22 mole (50 g) of 2,4,6-trichloronitrobenzene is added in portions to 150 ml of 3-amino-1-propanol heated to 80° C., with stirring. Heating is continued for 1 hour 30 minutes after the addition is complete. The reaction medium is poured into 300 g of ice-cold water. An oil which crystallizes on adding concentrated hydrochloric acid is obtained. The precipitate of the expected product is drained, washed with a 2N solution of hydrochloric acid and then with water to neutrality. After drying at 40° C. in the presence of phosphorous pentoxide, it is recrystallized from 96° ethanol. It melts at 127° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15][C:5]=3[N:6]([CH2:11][C:12](O)=O)[C:7]=2[CH:8]=[CH:9][CH:10]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:42]1([NH2:49])[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH2:48].C(O)(=O)C>C1COCC1.CCOC(C)=O>[NH:48]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:49]=[C:12]1[CH2:11][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=2[C:4]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15][C:5]1=2
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cccc(Br)c23)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(Cc3nc4ccccc4[nH]3)c3cccc(Br)c23)CC1
Temperature: 50 °C
Reaction time: 19 h
Yield: 59 %

Procedure:
A solution of (10-bromo-3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetic acid (0.152 g, 0.359 mmol) and triethylamine (0.052 mL, 0.038 g, 0.372 mmol, 1.04 equiv.) in THF (2 mL) was cooled to 0° C. under N2. Isobutyl chloroformate (0.048 mL, 0.051 g, 0.372 mmol, 1.04 equiv.) was added and the reaction mixture was stirred for 2.3 h. o-Phenylenediamine (0.0406 g, 0.375 mmol, 1.04 equiv.) and acetic acid (0.24 mL, 0.26 g, 4.25 mmol, 11.8 equiv.) were added, and the reaction mixture was heated to 50° C. The temperature of the reaction mixture gradually was increased to 64° C. over 3 h. After 19 h, the reaction mixture was cooled to rt. The reaction mixture was taken up in EtOAc, and the resulting solution was washed with water, saturated aq. NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product (0.1865 g) was chromatographed (SiO2 22 g, eluted with 5:1 toluene:acetone) to give tert-butyl 6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.105 g) in 59% yield. 1H NMR (300 MHz, CDCl3) δ 1.12, 3.20, 3.54, 3.68-3.74, 5.54, 5.58, 6.88, 7.20, 7.23-7.30.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:12]=[N:13][CH:14]=2)O1.Cl[C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]2[CH:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([CH:30]=[C:21]([C:9]3[CH:10]=[C:11]([C:15]([OH:18])([CH3:16])[CH3:17])[CH:12]=[N:13][CH:14]=3)[N:22]=2)[CH:25]=1
Reactant: Fc1ccc2nc(Cl)cn2c1
Reactant: CC(C)(O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(-c2cn3cc(F)ccc3n2)c1
Temperature: 100 °C

Procedure:
To a solution of the title compound from Example 2 Step D (0.1855 g, 0.704 mmol) and the title compound from Example 2 Step B (0.10 g, 0.586 mmol) in tetrahydrofuran (5.86 mL) were added palladium acetate (0.013 g, 0.059 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.048 g, 0.117 mmol), and potassium phosphate tribasic (0.373 g, 1.759 mmol). The resulting mixture was heated at 100° C. for 18 hours. The mixture was then cooled to room temperature, filtered with the aid of ethyl acetate, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (30-50% acetone in dichloromethane) provided the title compound: LCMS m/z 273.99 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=1.6 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.39 (t, J=2.0 Hz, 1H), 8.10 (t, J=2.6 Hz, 1H), 7.96 (s, 1H), 7.63 (dd, J=9.9, 4.8 Hz, 1H), 7.17-7.13 (m, 1H), 2.00 (br s, 1H), 1.68 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]3[CH:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=2)[CH2:2]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:15][C:13]1[O:14][C:10]2[CH:9]=[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[C:6]([O:5][CH:3]3[CH2:4][N:1]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:2]3)[C:11]=2[CH:12]=1
Reactant: CCOC(=O)c1cc(OC2CNC2)c2cc(C)oc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC2CN(S(C)(=O)=O)C2)c2cc(C)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of ethyl 4-(azetidin-3-yloxy)-2-methyl-1-benzofuran-6-carboxylate (324b) (200 mg, 0.73 mmol) in DCM containing TEA (0.4 mL, 2.9 mmol) was added methanesulfonyl chloride (0.07 mL, 0.87 mmol). The mixture was stirred at room temperature for 2 hrs. The reaction was diluted with DCM, washed with NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified via gradient silica gel chromatography using EtOAc/Hexanes (10/90 to 30/70) to provide the product (206 mg, 80%) as a white solid after evaporation of the solvents. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.34-1.51 (m, 3 H) 2.49 (s, 3 H) 2.89-3.07 (m, 3 H) 4.06-4.22 (m, J=9.23, 4.33 Hz, 2 H) 4.33-4.54 (m, 4 H) 5.07-5.23 (m, 1 H) 6.52 (s, 1 H) 7.02 (s, 1 H)l MS (ESI, pos): 354.
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[C:27]([C:42]#[N:43])=[N:28][N:29]([CH2:38][CH2:39][O:40][CH3:41])[C:30]=1[CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:41][O:40][CH2:39][CH2:38][N:29]1[C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:26]2[C:27]([C:42]([NH2:43])=[N:9][C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:28]1
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Reactant: COCCn1nc(C#N)c(Br)c1CC1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COCCn1nc2c(N)nc3ncccc3c2c1CC1CCOCC1
Temperature: 80 °C
Yield: 7.1 %

Procedure:
Hydrochloric acid (10 mL of 1M) was added to a solution of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (2.59 g, 10.9 mmol), and the resulting mixture was heated at 80° C. for 45 minutes and allowed to cool to room temperature. Potassium carbonate (3.60 g, 26.0 mmol) was added with stirring, and then DME (20 mL), 4-bromo-1-(2-methoxyethyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile (1.75 g, 5.33 mmol), and dichlorobis(triphenylphosphine)palladium(II) (190 mg, 0.27 mmol) were added. The reaction was carried out as described in Part C of Example 4. The crude product was purified by automated flash chromatography (eluting with 0% to 35% CMA in chloroform) followed by recrystallization from acetonitrile (30 mL) after hot filtration. The crystals were washed with cold acetonitrile and dried overnight in a vacuum oven at 60° C. to provide 0.13 g of 2-(2-methoxyethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine as light yellow needles, mp 230-233° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Cc1ccccc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1ccc(OCCCCl)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxy-2′-methylbiphenyl (0.55 g), potassium carbonate (2.07 g) and 1-bromo-3-chloropropane (1.48 mL) in N,N-dimethylformamide (20 mL) affords 913 mg of 4-(3-chloropropoxy)-2′-methylbiphenyl used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH2:30])[CH3:26].Cl.CCN(CC)CC>C1COCC1>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][NH:30][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:26]
Reactant: O=C(O)CCCc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
4-Phenylbutyric acid (2.46 g, 15 mmol) was dissolved in distilled THF (70 ml) in an argon atmosphere. After cooling in an ice bath, carbonyldiimidazole (CDI) (2.43 g, 1.5 mmol) was added and the mixture was stirred cold 1 hour and at room temperature 1 hour. The mixture was then cooled and glycine ethyl ester·HCl (2.09 g, 15 mmol) and distilled Et3N (2.1 ml, 15 mmol) were added. The mixture was left stirring overnight at room temperature. After removal of the solvent in vacuo, Et2O (200 ml) was added. The solution was washed with 1N HCl (70 ml), 0.5N NaOH (70 ml) and saturated NaCl solution (70 ml), dried (MgSO4) and freed of solvent in vacuo leaving title compound (3.13 g, 84%) as white crystalline material. TLC: silica gel, Et2O, UV; Rf : 0.58.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:42]=[CH:41][C:22]([O:23][C:24]2[C:29]([F:30])=[CH:28][C:27](/[CH:31]=[C:32](\[CH3:39])/[C:33]([N:35]=[C:36]([NH2:38])[NH2:37])=[O:34])=[CH:26][C:25]=2[F:40])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[N+:2]=[N-:3].[CH2:43]([OH:46])[C:44]#[CH:45].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:37][C:36]([NH2:38])=[N:35][C:33](=[O:34])/[C:32](/[CH3:39])=[CH:31]/[C:27]1[CH:28]=[C:29]([F:30])[C:24]([O:23][C:22]2[CH:41]=[CH:42][C:19]([S:16](=[O:18])(=[O:17])[NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]3[CH:45]=[C:44]([CH2:43][OH:46])[N:3]=[N:2]3)=[CH:20][CH:21]=2)=[C:25]([F:40])[CH:26]=1
Reactant: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1)C(=O)N=C(N)N
Reactant: C#CCO
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCn3cc(CO)nn3)cc2)c(F)c1)C(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 14 h
Yield: 30 %

Procedure:
To a mixture of (E)-3-(4-(4-(N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide (70 mg, 0.11 mmol) and propargyl alcohol (6.4 mg. 0.11 mmol) in t-butanol (0.22 mL) and water (0.22 mL) was added 1 M sodium ascorbate (11 μL, 0.011 mmol) and 0.3 M copper sulfate (3.6 μL, 0.0011 mmol) and the reaction was stirred at RT. After 14 hours, the product was purified by preparative HPLC to give the title compound (22 mg) as a TFA salt. 1H-NMR (400 mHz, CD3OD) δ 7.93 (s, 1H), 7.84 (m, 2H), 7.44 (s, 1H), 7.30 (m, 2H), 7.11 (m, 2H), 4.64 (d, j=0.6 Hz, 2H), 4.55 (t, j=5.0 Hz, 2H), 3.86 (t, j=5.0 Hz, 2H), 3.57 (m, 4H), 3.52-3.42 (m, 6H), 3.03 (t, j=5.4 Hz, 2H), 2.18 (d, j=1.3 Hz, 3H). MS (m/z): 668.14 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[CH3:27][NH:28][CH3:29].C(N(CC)CC)C.[C:37]([OH:46])(=[O:45])[CH:38]([CH:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]>C(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:11]([CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15]3)[C:17]=2[CH2:18][C:19]([N:28]([CH3:29])[CH3:27])=[O:20])=[CH:6][CH:7]=1.[CH:38]([OH:39])([C:37]([OH:46])=[O:45])[CH:40]([OH:41])[C:42]([OH:44])=[O:43]
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Reactant: CNC
Agent: Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)N(C)C)cc1
Temperature: 15 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
A suspension of 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-acetic acid (60 g; 0.21 mols) in methylene chloride (600 mL) is added dropwise with thionyl chloride (27.4 g; 0.23 mols) adjusting the addition according to the gas evolution and keeping the temperature below 35° C. The resulting dark suspension is refluxed for 30 minutes, then cooled to 10÷15° C. and added with dimethylamine hydrochloride (98% titre, 20.5 g, 0.25 mols). Keeping the temperature below 15° C., triethylamine (83.5 g, 0.82 mols) is dropped therein. After one hour at room temperature, water is added (200 mL), the phases are separated and the lower organic phase is washed with a 5% sodium carbonate aqueous solution (200 mL) and subsequently with water (200 mL). The organic phase is concentrated to a residue, which is redissolved in methanol (600 mL) under reflux, and added with natural tartaric acid (16.5 g, 0.11 mols). The resulting solution is slowly cooled to 0° C. and the precipitated solid is filtered under nitrogen and washed with cold methanol (2×30 mL). The humid solid is taken up in methanol (400 mL), refluxed until dissolution and added with active carbon (3 g). The hot clear solution is filtered, then slowly cooled at 0° C. and the precipitated solid is filtered under nitrogen and washed with cold methanol (2×30 mL), then dried at 50° C. under vacuum to obtain Zolpidem tartrate (52.4 g, 99.6% titre, 99.0% HPLC purity, 65.2% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(=O)C.[O:11]=[P:12]1([CH2:26][OH:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13]1>C(N(CC)CC)C>[O:11]=[P:12]1([CH:26]=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13]1
Reactant: O=P1(CO)Oc2ccccc2-c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CP1(=O)Oc2ccccc2-c2ccccc21
Reaction time: 0.17 h

Procedure:
Purified dichloro methane anhydride 100 ml is cooled using dry ice and acetone. When the cooling is completed, oxalyl chloride 42.5 ml (0.05 mol) and dimethyl sulfur oxide 5.76 ml (0.08 mol) are added. Thereafter, they are stirred for 10 minutes. Then, (10-oxo-10H-9-oxa-10-phosphaphenanthrene-10-yl)-methanol (compound F) 10 g (0.04 mol) is added thereto. Thereafter, they are stirred for 1 hour. Then, triethylamine 22 ml is slowly added thereto. Thereafter, they are stirred at a normal temperature for 12 hours. When the reaction is completed, distilled water 100 ml is added thereto. Thereafter, solution is extracted using dichloro methane. The extracted solution is processed using 1N-hydrochloric acid water, saturated sodium bicarbonate solution, saturated brine water, or the like, and is dried using magnesium sulfate anhydride. The dried solution is filtered under reduced pressure and evaporated under reduced pressure to obtain brown solution. The obtained product is used for reaction in immediately subsequent step.