Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2nc3ccccc3o2)ccc1CBr

Procedure:
To a solution of 5.1 gm. of 2-(3-fluoro-4-methylphenyl)benzoxazole in 60 ml. of carbon tetrachloride is added 6.23 gm. N-bromosuccinimide and 100 mg. of dibenzoyl peroxide. The reaction mixture is refluxed for 6 hours, filtered to remove succinimide and the filtrate concentrated to dryness. The residue is chromatographed on 500 gm. of silica gel. Elution with 1% ether in petroleum ether gives 2-(4-bromomethyl-3-fluorophenyl)benzoxazole, m.p. 150°-152° C.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:28]=[C:27]([Cl:37])[C:26]=1[CH3:38].CCN(CC)CC>CN(C=O)C>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]2([C:33]([F:36])([F:34])[F:35])[O:13][N:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=4[CH:10]=3)[CH2:32]2)[CH:28]=[C:27]([Cl:37])[C:26]=1[CH3:38]
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Reactant: C=C(c1cc(Cl)c(C)c(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cc(C2(C(F)(F)F)CC(c3ccc4c(c3)C(C)(C)OB4O)=NO2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
The mixture of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (62 mg, 0.3 mmol) and NCS (48 mg, 0.36 mmol) in DMF (2 mL) was stirred at rt overnight. To the mixture was added 1,3-dichloro-2-methyl-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (75 mg, 0.3 mmol) and Et3N (0.1 mL) and the mixture was stirred at rt for 4 h. It was partitioned between EA and H2O. The organic layer was washed with H2O, brine, dried over Na2SO4, concentrated under vacuum. The residue was purified to give the desired product (30 mg, 21.8% yield).
Reaction SMILES: [C:1]([O:4][OH:5])(=[O:3])[CH3:2].[C:6]1(=[O:13])[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(=O)CCCCC1.C(OCC)(=O)C>[C:6]1(=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1.[C:1]([O:4][OH:5])(=[O:3])[CH3:2].[C:1]([OH:4])(=[O:3])[CH2:2][CH2:9][CH2:8][CH2:7][C:6]([OH:13])=[O:12]
Reactant: O=C1CCCCCO1
Agent: CC(=O)OO
Solvent: CCOC(C)=O
Solvent: O=C1CCCCC1
Product: O=C(O)CCCCC(=O)O

Procedure:
60 g/hour of cyclohexanone and 170.5 g/hour of a solution of ethyl acetate used as a solvent and containing 30% of peracetic acid (51.4 g/hour of pure peracetic acid which corresponds to 1.1 mole based on one mole of cyclohexanone) were introduced in a flowing-type reactor of 2 liters. The reaction was conducted under a reaction temperature of 50° C. The composition of the solution obtained was ε-caprolactone: 28.78%, unreacted cyclohexanone: 0.52%, unreacted peracetic acid: 1.31%, by-produced adipic acid: 0.59%, caprolactone polymers: 0.30%, acetic acid: 21.16% and ethyl acetate (which was the solvent): 47.34%.
Reaction SMILES: ClCC1(COC2C=CC(Cl)=CC=2Cl)CO1.[Cl:16][C:17]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:18]=1[O:19][CH2:20][C:21]1([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[CH2:23][O:22]1.[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][C:17]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:18]=1[O:19][CH2:20][C:21]([OH:22])([CH2:23][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33]
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(OCC2(COc3ccc(Cl)cc3Cl)CO2)c(Cl)c1
Agent: ClCC1(COc2ccc(Cl)cc2Cl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(COc1ccc(Cl)cc1Cl)(COc1ccc(Cl)cc1Cl)Cn1cncn1

Procedure:
23.5 g of a mixture of 2-chloromethyl-2-(2,4-dichlorophenoxymethyl)-oxirane and 2,2-bis(2,4-dichlorophenoxymethyl)-oxirane are added dropwise to a solution of 20.7 g (0.3 mole) of 1,2,4-triazole and 13.8 g (0.1 mole) of potassium carbonate in 200 ml of acetone. The reaction mixture is stirred under reflux for 20 hours. It is then filtered cold and the filtrate is concentrated in vacuo. The residue is dissolved in chloroform and the solution is washed with water, dried over sodium sulphate and purified and separated by chromatography (silica gel 60 Merck). Chloroform is first used as the eluting agent. The eluate thereby obtained is concentrated by distilling off the solvent and the residue is stirred with diethyl ether. 4.8 g of 1,3-bis-(2,4-dichlorophenoxy)-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-propane (Example 5) of melting point 136° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH2:16])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]([F:26])([F:25])[C:19]([OH:24])([CH3:23])[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CO>[NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:20](=[O:21])[C:19]([OH:24])([CH3:23])[C:18]([F:26])([F:25])[F:17])=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(O)(C(=O)NNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Temperature: 0 °C

Procedure:
A cooled (0° C.) solution of 3-amino-6-bromo-5-(trifluoromethyl)picolinohydrazide (Intermediate H) (15 g, 50.2 mmol) in dry NMP (50 ml) was treated with 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (8.72 g, 55.2 mmol), HATU (20.98 g, 55.2 mmol) followed by dropwise addition of TEA (15.38 ml, 110 mmol) over 10 minutes. The orange solution was stirred at 0° C. and allowed to warm to RT and stirred for 3 days. The reaction mixture was partitioned between EtOAc (200 mL) and 1M NaOH (200 mL), shaken and separated. The organic portion washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to give an orange oil. The oil was taken up in methanol (50 mL) and triturated with water (300 mL) to afford the title compound as a yellow solid;
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:4](=[O:5])[CH:3]=1.C(O)(=O)CCCCC(O)=O>>[CH3:1][C:2]1[CH2:3][C:4](=[O:5])[CH2:6][C:7]([CH3:10])([CH3:9])[CH:8]=1
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: O=C(O)CCCCC(=O)O
Product: CC1=CC(C)(C)CC(=O)C1

Procedure:
α-isophorone (α-IP) and 7% by weight of adipic acid relative to the amount of α-isophorone were fed to the bottom of the oldershow distilling column (30 plates, 50 mmφ) equipped with a vacuum jacket, and the bottom was heated to start the mixture refluxing. Thereafter, β-isophorone (β-IP) was obtained in the form of a distillate at a distilling rate of 30 g/hr while supplying α-IP to the bottom of the distilling column at a supply rate of 30 g/hr. The distilling column was manipulated at an atmospheric pressure and a reflux ratio of 63. Moreover, the residence time of α-IP at the bottom was 2 hours, the temperature of the bottom was 220° C., and the temperature of the distillate was 183° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][C:10]=1[CH3:17])([CH3:7])[CH3:6])[CH3:2].[CH3:19][O:20][CH2:21][CH2:22][C:23]1[C:28]([C:29](O)=[O:30])=[CH:27][N:26]=[C:25]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[N:24]=1.COC(=O)CC(=O)CCOC>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:29]([C:28]2[C:23]([CH2:22][CH2:21][O:20][CH3:19])=[N:24][C:25]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=3)=[N:26][CH:27]=2)=[O:30])=[CH:11][C:10]=1[CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1C
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Agent: COCCC(=O)CC(=O)OC
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 97B]) was reacted with 4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 5-methoxy-3-oxo-pentanoic acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49]Cl.COC1C=CC(CCl)=CC=1>>[F:44][C:45]([F:54])([F:55])[C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: COc1ccc(CCl)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2cccc(C(F)(F)F)c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 7 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-(trifluoromethyl)benzyl chloride to replace 4-methoxybenzyl chloride, 1′-[3-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (92%) as a colorless solid: mp 131-134° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ7.62-7.43 (m, 4H), 7.25-7.18 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.23 (s, 1H), 5.14 (d, J=15.9 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.88 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.23-4.18 (m, 2H), 4.15-4.11 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 144.8, 141.8, 138.5, 137.0, 132.3, 131.4 (q, J=32.4 Hz), 130.7, 129.7, 129.0, 124.9 (q, J=3.7 Hz), 124.25, 124.22 (q, J=3.7 Hz), 124.0 (q, J=272.4 Hz), 123.8, 120.9, 111.6, 109.1, 99.6, 80.2, 64.7, 64.0, 58.2, 43.8; MS (ES+) m/z 453.9 (M+1).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:16]3)[CH:12]=[CH:11][N:10]=2)=CC=1.C(O)(=O)C>C(O)(C(F)(F)F)=O>[C:21]1([NH:20][C:17]2[N:18]=[CH:19][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=3)[N:16]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CNc2cc(-n3cnc(Nc4ccccc4)n3)ccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Nc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Reaction time: 16 h

Procedure:
[1.5 g, 4.03 mMol] of (4-Methoxy-benzyl)-[4-(3-phenylamino-[1,2,4]triazol-1-yl)-pyridin-2-yl]-amine was dissolved in 25 mL of TFA and stirred at 40 C. in a sealed tube for 16 hrs. Then, 10 mL of glacial acetic acid was added and the mixture was stirred at 40 C. for an additional 24 hr. The solvent was removed under reduced pressure and the residue triturated with MTBE, The crude material was treated with water and neutralized with 11.4N ammonium hydroxide to pH 9. The resulting solid was isolated via suction filtration and washed with water. This crude product was treated with 0.25N HCl and particulates removed via suction filtration. The filtrates were neutralized with conc. ammonium hydroxide to a pH of 10 and the mixture was extracted with chloroform twice. The organics were combined and washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Tan powder collected; 300 mg (33%). 1H NMR 500 MHz (DMSO-d6) ∂ 6.22(s ex, 2H), 6.88(m, 2H), 7.09d, 1H), 7.26(t, 2H), 7.67(d, 2H), 7.97(d, 1H), 9.14(s, 1H), 9.52(s ex, 1H). LC/MS [M+H+]253.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1.O.[NH2:24][NH2:25]>CO>[Cl:10][C:9]1[C:4]([C:3]([NH:24][NH2:25])=[O:2])=[N:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][CH:8]=1
Reactant: NN
Reactant: COC(=O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl

Procedure:
3-chloro-6- [3-(trifluoromethyl)phenoxy]-2-picolinic acid methyl ester (0.72 g, 0.00217 mol) was dissolved in methanol (10 ml), and then mixed with hydrazine monohydrate (1.087 g, 0.00217×10 mol). The resultant mixture was refluxed for about 3 hours. The obtained reaction solution was concentrated, and the obtained residues were distributed in ethyl acetate-saturated sodium bicarbonate water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OCC5C=CC=CC=5)[CH2:25][CH2:24]4)[C:20]([F:40])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:21]2[C:20]([F:40])=[CH:19][N:18]=[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:15][CH:14]=3)[N:22]=2)[CH2:24][CH2:25]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(=O)OCc5ccccc5)CC4)n3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(N)CC4)n3)cc2)CC1
Yield: 85.5 %

Procedure:
A solution of benzyl 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-fluoropyrimidin-4-yl)piperidin-4-ylcarbamate (370 mg, 0.676 mmol) and Pd—C (10%, 55 mg) in MeOH (12 mL) was hydrogenated under balloon hydrogen for 20 h. It was then filtered through celite. The filtrate was concentrated in vacuo to give the titled compound (239 mg). MS 414.3 (M+H); UV 202.8, 268.8 nm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]([CH3:16])=[C:9]2[C:10](=[O:14])[NH:11][CH2:12][CH2:13][N:8]2[N:7]=1)=O)[CH3:2].Cl[C:18]1[C:19](CO)=NN2CCN[C:23](=O)[C:22]=12.ClC1C(COC2C=CC=CC=2)=NN2CCNC(=O)C=12>>[CH3:16][C:15]1[C:6]([CH2:4][O:3][C:1]2[CH:23]=[CH:22][CH:18]=[CH:19][CH:2]=2)=[N:7][N:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[C:9]=12
Reactant: CCOC(=O)c1nn2c(c1C)C(=O)NCC2
Reactant: O=C1NCCn2nc(CO)c(Cl)c21
Agent: O=C1NCCn2nc(COc3ccccc3)c(Cl)c21
Product: Cc1c(COc2ccccc2)nn2c1C(=O)NCC2

Procedure:
The compound was prepared from 3-methyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester using the methods described in the preceding examples 77 (3-chloro-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one) and 78 (3-chloro-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: O=C(Cl)C1CC1
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Solvent: c1ccncc1
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.6 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (270 mg, 0.59 mmol) in pyridine (6.0 mL) was added cyclopropanecarbonyl chloride (70 μL, 0.767 mmol), and the mixture was stirred at room temperature for 12 hr. Cyclopropanecarbonyl chloride (35 μL, 0.383 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (50 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (188 mg, 61%) as a colorless powder.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[C:22]=2[F:31])=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:10])[CH3:7]>CC#N>[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:21]2[C:22]([F:31])=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[C:26]=2[Cl:4])=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:10])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2cccnc12
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2cccnc12
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
Sulfuryl chloride (75 μL, 0.93 mmol) was added dropwise to a cold (−20° C.) solution of 5-(2-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 176.3) (330 mg, 0.93 mmol) in CH3CN (6 mL). The reaction mixture was stirred for 10 min at −20° C., quenched by addition of a saturated solution of NaHCO3, and concentrated. The residue was diluted in EtOAc and a saturated solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 240 mg of the title compound as a white solid. Title compound: ESI-MS: 390.1 [M+H]+; tR=3.98 min (System 1); TLC: Rf=0.15 (Hex/EtOAc, 3:2).
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:10])[O:6][CH2:7][CH2:8][CH3:9])#[N:3].[N:11]#[C:12]N>>[C:12]([N:10]=[C:5]([O:6][CH2:7][CH2:8][CH3:9])[CH2:4][C:2]#[N:3])#[N:11]
Reactant: CCCOC(=N)CC#N
Reactant: N#CN
Agent: Cl
Product: CCCOC(CC#N)=NC#N
Yield: 72.2 %

Procedure:
3.25 g of n-propyl cyanoacetimidate hydrochloride and 1.26 g of cyanamide were treated with the same manner as in Example 1 and 2.18 g of oily n-propyl N-cyanocyanoacetimidate was obtained (yield 72.1%). The structure of this compound was confirmed by IR and NMR. Analysis calculated for C7H9N3O C 55.62, H 6.00, N 27.80, found C 54.80, H 6.27, N 27.13.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[C:22]([SH:23])=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.ClCCl>[Cl:9][C:5]1[N:4]=[N:3][C:2]([S:23][C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:16])=[N:7][C:6]=1[Cl:8]
Reactant: Clc1nnc(Cl)c(Cl)n1
Reactant: Cc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccccc1Sc1nnc(Cl)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 116.5 %

Procedure:
3,5,6-Trichloro-1,2,4-triazine (0.50 g) was dissolved in dry tetrahydrofuran (8 ml) and dry potassium carbonate (0.37 g) and 4Å molecular sieves (180 mg, activated overnight at 180° C.) were added. The stirred mixture was cooled to 0° C. and a solution of o-thiocresol (0.36 g) in dry tetrahydrofuran (4 ml) was added dropwise. After 45 minutes at 0-5° C. and standing overnight at 10° C., the mixture was diluted with dichloromethane (20 ml) and filtered through Hyflo Supercel filter aid covered with a layer of Merck silica 60. The filtrate was concentrated under reduced pressure to afford a single dichloro-(2-methylphenylthio)-1,2,4-triazine (unidentified regioisomer) as a yellow oil (0.86 g) which crystallised on standing. Recrystallisation from ether-n-hexane yielded a pale yellow powder (0.57 g, 77%); m.p. 93-95° C.; IR max (nujol mull): 1460, 1250 cm-1 ; 1H NMR: δ2.38 (3H,s), 7.24-7.37(1H,m), 7.37-7.54(3H,m) ppm.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>C1COCC1>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH2:29][CH2:30][NH:31][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: O=c1[nH]nc2c(Br)nc(-c3ccc(Cl)cc3)cn12
Reactant: NCCNc1nc2ccccc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc2c(NCCNc3nc4ccccc4s3)nc(-c3ccc(Cl)cc3)cn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 50 mg of the product of Step A, 43 mg of N1-benzothiazol-2-yl-ethane-1,2-diamine, and 124 mg of triethylamine in THF (1.0 mL) was heated to reflux. After 16 h, the reaction mixture was cooled to ambient temperature and then partitioned between EtOAc and water. The organic layer was dried over sodium sulfate, filtered, and concentrated to a residue that was purified by silica gel chromatography to afford the title compound as a white solid. MS (M+H+)=438.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43](Cl)=[O:44].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:43]([C:34]1[CH:35]=[CH:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:44])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2c1
Yield: 64.3 %

Procedure:
A solution of 249 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 106 mg of 2-naphthoyl chloride and 72 mg of diisopropylethylamine in 10 ml of dry dichloromethane was stirred at 20° C. for 20 hours. The gelatinous reaction mixture was partitioned between dichloromethane and water. The organic phase was evaporated and the resulting oil was crystallized from ethyl acetate/n-hexane to give 215 mg of N-[2(R)-hydroxy-3(S)-[[N-(2-naphthoyl)-L-asparaginyl]amino]-4-phenylbutyl]-L-proline tert.butyl ester, as a white solid; MS: m/e 603 [M+H]+.