Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:4].[O:12]=[C:13]([CH3:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].N12CCCNC1=NCCC2>C(#N)C>[C:13]([CH:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:4])[C:15]([O:17][CH3:18])=[O:16])(=[O:12])[CH3:19]
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: COC(=O)CC(C)=O
Agent: C1CN=C2NCCCN2C1
Solvent: CC#N
Product: COC(=O)C(CC(=O)c1cccc(F)c1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 21.7 mg portion of 2-bromo-1-(3-fluorophenyl)ethanone and 13.9 mg of methyl 3-oxobutanoate were dissolved in 1.0 ml of acetonitrile, and 115 mg of a 1,5,7-triazabicyclo[4.4.0]dec-5-ene-carrying resin (trade name: 1,5,7-Triazabicyclo[4.4.0]dec-5-ene bond to polystyrene crosslinked with 2% DBV, Fluka, Switzerland) was added, followed by stirring at room temperature for 3 hours. Then, the reaction liquid was filtered. By concentrating the filtrate under a reduced pressure, methyl 2-acetyl-4-(3-fluorophenyl)-4-oxobutanoate was obtained as a crude product. A 0.500 ml acetic acid solution of 21.1 mg of 4-fluorophenethylamine hydrochloride was added to the resulting crude product, followed by stirring overnight at 100° C. By evaporating the solvent under a reduced pressure, methyl 5-(3-fluorophenyl)-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was obtained as a crude product. The resulting crude product was dissolved in a mixed solvent of 0.500 ml tetrahydrofuran and 0.500 ml methanol, and 0.500 ml of a 2 M sodium hydroxide aqueous solution was added, followed by stirring overnight at 60° C. By adding 1 M hydrochloric acid to the reaction liquid at room temperature, the water layer was acidified, followed by extraction with chloroform. By evaporating the solvent of the organic layer under a reduced pressure, 5-(3-fluorophenyl)-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylic acid was obtained as a crude product. A 0.600 ml portion of a N,N-dimethylformamide solution of 24 mg 1,1′-carbonylbis-1H-imidazole was added to the resulting crude product and stirred at 50° C. for 2 hours. A solution prepared by adding 5.3 mg of guanidine hydrochloride to 0.400 ml N,N-dimethylformamide solution of 20 mg of sodium hydride (60% dispersion in oil) and stirring at room temperature for 30 minutes was added to this reaction liquid at room temperature, followed by stirring overnight at room temperature. The solvent was evaporated under a reduced pressure, and water was added to the residue, followed by extraction with chloroform. The solvent of the organic layer was evaporated under a reduced pressure, and the resulting residue was purified by a fractional high performance liquid chromatography (acetonitrile/a 0.1% trifluoroacetic acid aqueous solution) to obtain 3.7 mg of N-(diaminomethylene)-5-(3-fluorophenyl)-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[Cl:17].[Li+].[OH-].C1COCC1.CO.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Cl:17]
Reactant: COC(=O)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound 27c (662 mg, 2.0 mmol) and LiOH (192 mg, 8 mmol) in a solvent mixture of THF/MeOH/H2O (3/3/3 mL) was stirred at room temperature for 4 h, then acidified with 15% citric acid in H2O. The mixture was extracted with EtOAc (3×), and the combined extracts washed sequentially with water and brine. The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant crude compound 3b was dried under reduced pressure for 18 h and used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH:27]=O)=[CH:23][NH:24]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](/[CH:27]=[CH:14]/[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:15])=[CH:23][NH:24]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2c(C=O)c[nH]c2c1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1ccc2c(/C=C/C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2c1
Yield: 32 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (659 mg) and 6-methoxyindole-3-carboxaldehyde (550 mg) except that the reaction solution was concentrated under reduced pressure, that the residue was purified by silica gel column chromatography, and that the obtained crude crystals were recrystallized from ethanol, to give Compound 39 (369 mg).
Reaction SMILES: B(Br)(Br)Br.[C:5]1([C:11]2(C)[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([O:21]C)[CH:15]=[CH:16][CH:17]=3)[NH:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:24](Cl)Cl>>[C:5]1([C:11]2[C:20]([CH3:24])=[CH:19][C:18]3[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc2c1NC(C)(c1ccccc1)C=C2
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cc1cc2cccc(O)c2nc1-c1ccccc1
Reaction time: 3 h
Yield: 64 %

Procedure:
17.6 ml (180 mmol) of boron tribromide are added dropwise, at −30° C., to a solution of 21.2 g (85 mmol) of 2-phenyl-2-methyl-8-methoxyquinoline in 500 ml of methylene chloride. The cooling bath is then removed and the reaction medium is stirred for 3 hours until it has returned to ambient temperature. The reaction mixture is then poured onto ice and the medium is basified using sodium hydrogencarbonate. The medium is subsequently extracted with 3×200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel chromatography (eluent: ethyl acetate/cyclohexane 3/7) to give 12.7 g of 2-phenyl-3-methyl-8-hydroxyquinoline in the form of a colorless oil. (Yield: 64%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>O1CCCC1.[Pt](=O)=O>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CCOCC1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CCOCC1

Procedure:
22.80 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(tetrahydropyran-4-yl)methoxy]quinazoline are hydrogenated in 300 ml of tetrahydrofuran in the presence of 3.50 g of platinum dioxide at ambient temperature until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is evaporated to dryness using the rotary evaporator. The residue is stirred with diethylether, suction filtered, washed with diethylether and dried at ambient temperature. Yield: 19.95 g (93% of theory); mass spectrum (ESI+): m/z=403, 405 [M+H]+; melting point: 221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25]C)=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.ClC1C=C[N:32](CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)[C:31](=O)[N:30]=1.N1C=NC=N1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:25]=[N:32][CH:31]=[N:30]3)=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Reactant: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: c1nc[nH]n1
Solvent: CN(C)C=O
Product: O=c1nc(-n2cncn2)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and 1H-1,2,4-triazole in DMF. M/e+ 404 for C20H15ClN7O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 9.24 (d, J=1.8 Hz, 1H), 8.33 (d, J=6.6 Hz, 1H), 8.18 (d, J=1.8 Hz, 2H), 8.06 (d, J=1.8 Hz, 1H), 7.67 (m, 1H), 7.66 (dd, J=8.4, 1.8 Hz, 1H), 7.49 (dd, J=8.4, 1.8 Hz, 2H), 7.34 (m, 1H), 6.95 (t, J=6.6 Hz, 1H), 6.90 (dd, J=7.3, 1.8 Hz, 1H), 5.27 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([Cl:26])=[C:6]([CH:25]=1)[O:7][C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[S:14][C:10]=2[C:9]=1[C:23]#[N:24].[N:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)=[C:29]=[O:30]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:5]1[CH:4]=[C:3]([F:27])[C:2]([NH:1][C:29](=[O:30])[NH:28][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:40])[F:39])=[CH:33][CH:32]=2)=[CH:25][C:6]=1[O:7][C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[S:14][C:10]=2[C:9]=1[C:23]#[N:24]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2cc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.4 %

Procedure:
N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (150 mg, 0.372 mmol) produced in Example 23(vi) was dissolved in N,N-dimethylformamide (1.5 mL), 1-isocyanato-4-(trifluoromethyl)benzene (69 μL, 0.484 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (115 mg, 52%) as a white powder.
Reaction SMILES: [NH:1]([C:35]([CH3:37])=[O:36])[C@@H:2]([C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@@H:21]1[C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[OH-].[Na+].C(OC(C)C)(C)C.Cl>ClCCl.CO>[NH:1]([C:35]([CH3:37])=[O:36])[C@@H:2]([C:18]([N:20]1[CH2:34][CH2:33][CH2:32][C@@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The Ac-D-Lys(Z)-D-Pro-OBzl compound obtained at the previous steps (in theory: 230 mmol) is mixed with 313 ml of methanol, added with 313 ml of 1N NaOH (313 mmol, 1.36 eq), and stirred overnight at room temperature. The reaction completion is CCM controlled. Thereafter, diisopropyl ether is added (313 ml, 11 vol.), the medium is decanted and the aqueous phase is extracted again three times with 3×150 ml of diisopropyl ether. The aqueous phase is then poured onto a blend of 540 ml of dichloromethane and 70 ml of aqueous 4N HCl (1.2 eq). The blend is stirred for 15 minutes and decanted. The separated organic phase is washed with water followed by a NaCl saturated aqueous solution (110 ml, 4 vol. each time). The organic phase is dried on Na2SO4 and vacuum concentrated (40° C. max, 50 mbar max.). The thus obtained product 94.25 g has the form of a foam (yield=98% calculated based on the involved Boc-D-Lys(Z)-OH).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH2:3]1.[CH3:35][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.[NH4+].[Cl-]>CN(C=O)C.C1COCC1>[CH3:35][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4]1=[O:34]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h

Procedure:
To a stirring solution of 2.65 g (5.78 mmol) of 2-(2,4-Dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 80 mL of DMF at 0° C. is added 6.36 mL (6.36 mmol) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 10 min, then 400 mL (6.36 mmol) of methyl iodide is added neat. The resulting solution is stirred at RT for 45 min then poured into 100 mL NH4Cl. The reaction mixture is concentrated to remove the DMF, diluted with 500 mL of H2O and extracted with EtOAc (3×200 mL). The organics were dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash chromatography using EtOAc as eluent afforded 2.52 g of 2-(3-Methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as a white foam: 1H NMR (CDCl3, 400 MHz) δ8.50 (s, br, 2H), 7.79 (d, 1H, J=8.1), 7.43 (d, 1H, J=8.1), 7.36-6.94 (m, 8H), 6.88 (d, 1H, J=8.8), 4.98 (m, 1H), 4.26 (m, 2H), 3.85 (s, 3H), 3.54 (q, 1H, J=7.1), 1.42 (d, 3H, J=7.1), 1.07 (m, 6H); low resolution MS (FAB)m/e 473 (MH+); Anal. (C27H28N4O4) Calcd. C, 68.63; H, 5.97; N, 11.86 Found C, 66.91; H, 6.13; N, 11.29.
Reaction SMILES: [Na].[K].CN(CCN(C)C)C.[CH2:11]=[CH:12][CH:13]=[CH2:14].[C:15]1([CH3:22])[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>O>[CH3:11][C:12]1[C:20]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:21])=[CH:15][CH:22]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1C
Reactant: C=CC=C
Agent: CN(C)CCN(C)C
Agent: [K]
Agent: [Na]
Solvent: O
Product: C=CCCCc1ccccc1C
Yield: 59.7 %

Procedure:
Using the equipment and procedure described in Example I a run was made using an alloy of 0.1% sodium and 0.1% potassium based on the weight of the xylene and another run with the same alloy was made adding 0.09% TMEDA. Both runs were made using butadiene having 155 ppm water which decreased activity but the effect of the amine cocatalyst is indicated by a trans:cis ratio 2.11 compared to 1.35 for the alloy alone, and by cumulative yield of 59.7% 5-OTP compared to 40% for the alloy alone. Other examples are listed in Table I.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[S:8][C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH2:19])(=[O:18])=[O:17])=[N:6][N:5]=1.[CH3:20]I>CO>[CH3:20][S:3][C:4]1[S:8][C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH2:19])(=[O:18])=[O:17])=[N:6][N:5]=1
Reactant: NS(=O)(=O)c1ccccc1Cc1nnc(S)s1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(Cc2ccccc2S(N)(=O)=O)s1
Reaction time: 0.08 h
Yield: 15.3 %

Procedure:
To a solution containing 1.0 g of potassium hydroxide in 50 ml of methanol was added 5 g of the crude oxadiazole prepared in Example 2. After stirring about five minutes, 3.5 g of methyl iodide was added. The solution was refluxed one hour, cooled to 30°, an extra 10 ml of methyl iodide was added, and the solution was refluxed an additional two hours, then concentrated in vacuo. After water (about 150 ml) was added to the residue, the suspension was extracted with methylene chloride. The methylene chloride solution was dried (MgSO4), concentrated in vacuo, and the residue was recrystallized from acetonitrile to give 0.8 g of the subject compound; m.p. 175°-178° C. NMR(CDCl3, DMSO-d6): δ 2.8(s, SCH3); 4.9(s, CH2); 7.3(s, NH2); 7.4-8.3 (m, ar) ppm. Mass spectrum by direct probe using electron impact ionization showed highest significant m/e 301.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:13].[OH-]>O>[NH2:13][CH2:12][C@H:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC[C@H](O)COCc1ccccc1
Yield: 98 %

Procedure:
ER-886133 and ER-886134: A solution of (S)-2-((benzyloxy)methyl)oxirane (65 g, 0.396 mol) and 28% NH4OH in water was stirred at rt for 14 h after which time the completed reaction was concentrated and azeotroped two times with toluene (150 mL each) to obtained (S)-1-amino-3-(benzyloxy)propan-2-ol (70.6 g, 0.390 mol, 98% yield) as a crude white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[C:8](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[CH:7]=[CH:6]2.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:24][C:23](=[O:25])/[CH:22]=[CH:21]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: COc1ccc(-c2c(/C=C/C(=O)O)ccc3cc(OC)ccc23)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(-c2c(/C=C/C(=O)Oc3ccc([N+](=O)[O-])cc3)ccc3cc(OC)ccc23)cc1

Procedure:
As in Example 113, (E)-3-[6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid (1.4 g) was reacted with 4-nitrophenol (0.64 g) in dichloromethane (25 mL) in the presence of 1,3-dicyclohexylcarbodiimide (0.87 g) overnight at room temperature to give, after the normal work up and crystallization of the crude product from 2-propanol, 1.6 g of (E)-3-[6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid 4-nitrophenyl ester, mp 160°-161° C. Anal. Calcd for C27H21NO6 : C, 71.20; H, 4.65; N, 3.08 Found: C, 70.87; H, 4.89; N, 3.06
Reaction SMILES: NC[C:3]1O[C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:5][CH:4]=1.C([O:20][CH:21](C)C)(C)C>C(O)C>[NH2:16][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[CH:5]=[C:4]([CH2:3][NH:9][C:10](=[N:13][C:14]#[N:15])[S:11][CH3:12])[O:20][CH:21]=2)[N:9]=1)[NH2:15]
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: CC(C)OC(C)C
Solvent: CCO
Product: CSC(=NC#N)NCc1cc(-c2csc(N=C(N)N)n2)co1
Temperature: 25 °C

Procedure:
A mixture of 4-(5-aminomethylfuran-2yl)-2-(diaminomethyleneamino)thiazole (8.00 g) and dimethyl-N-cyanodithioiminocarbonate (2.54 g) in ethanol (80 ml) was refluxed for two hours with stirring. After cooling to room temperature, diisopropyl ether (80 ml) was added and the resulting precipitate was collected filtration. Recrystallization from a mixture of N,N-dimethylformamide and ethyl acetate to give 2-(diaminomethyleneamino)-4-[5-(3-cyano-2-methyl-1-isothioureido)methylfuran-3-yl]thiazole (10.2 g).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:14]1([C:19](N2C=CN=C2)=[S:20])C=CN=C1.O.[NH2:27]N>C1COCC1>[NH:14]([C:19]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[S:20])[NH2:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=S)NN)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
TEA (2.1 mL, 0.015 mol) was added to a solution of tert-butyl piperazine-1-carboxylate (1.86 g, 0.01 mol) and di-(1H-imidazol-1-yl)methanethione (2.67 g, 0.015 mol) in THF (30 mL) at rt. The reaction mixture was stirred at rt for 2 hrs., then hydrazine hydrate (0.73 mL, 0.015 mol) was added. The resultant solution was stirred at rt for another 2 hrs. The reaction mixture was quenched with saturated sodium chloride (15 mL) and extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, concentrated and recrystallized (3:1 petroleum ether/EtOAc) to afford tert-butyl 4-(hydrazinecarbonothioyl)piperazine-1-carboxylate (2.2 g, 85%) as a light yellow solid.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:12])[C@H:6]([CH2:8][CH2:9][CH2:10][NH2:11])[NH2:7].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O)([O-:15])=[O:14]>C(N(CC)CC)C>[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]1[CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N+:13]([O-:15])=[O:14])[N:11]2[CH2:10][CH2:9][CH2:8][C:6]2([C:5]([O:4][CH3:3])=[O:12])[NH:7]1)([O-:15])=[O:14]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H](N)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)C12CCCN1C(c1ccccc1[N+](=O)[O-])C(c1ccccc1[N+](=O)[O-])N2
Temperature: 0 °C

Procedure:
In a 250 ml round-bottomed flask equipped with a magnetic stirrer were taken a mixture of ornithine methyl ester dihydrochloride (5.0 g) and 2-nitrobenzaldehyde (7.5 g) in MDC (70 ml). The suspension was stirred at 0° C. for 15 mts. Triethylamine (4.64 g in 10 ml MDC) was added slowly. The reaction mixture was then allowed to stir at RT overnight. The reaction mixture was diluted with MDC, washed with water twice and dried over sodium sulfate. MDC was evaporated to give the crude product which was crystallized from methanol to give a white crystalline solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].C(O)(C)(C)C.F[C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[C:39]([CH:54]3[CH2:56][CH2:55]3)=[N:40][N:41]4[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O>[CH:54]1([C:39]2[C:38]3[C:42](=[CH:43][CH:44]=[CH:45][C:37]=3[NH:36][C:34]([C:31]3[N:28]4[CH:29]=[CH:30][C:25]([O:18][CH2:17][CH2:16][N:13]5[CH2:12][CH2:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH2:15][CH2:14]5)=[CH:26][C:27]4=[N:33][CH:32]=3)=[O:35])[N:41]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=3)[N:40]=2)[CH2:56][CH2:55]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Reactant: CC(C)N1CCN(CCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C(C)C)CC6)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
A one dram vial was charged with solid potassium tert-butoxide (55 mg, 0.49 mmol), 2-(4-isopropylpiperazin-1-yl)ethanol (0.099 g, 0.57 mmol), and tert-butanol (0.3 mL, 3.4 mmol). The mixture was stirred at ambient temperature for 30 minutes. 7-Fluoro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.034 g, 0.077 mmol) was added in one portion. The mixture was heated at 90° C. with stirring for 16 hours. The mixture was cooled to ambient temperature and diluted with water until a precipitate formed. The precipitate was collected by filtration and dried under high vacuum to give the product (0.019 g). MS (APCI), positive scan, m/z=593.1 (M+H).