Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H][H]>CO.[Pd]>[CH2:17]([NH:24][C@@H:2]1[CH2:7][CH2:6][C@H:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C(C(=O)OC)C1CCC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C(=O)OC)[C@H]1CC[C@@H](NCc2ccccc2)CC1

Procedure:
34.0 g of dimethyl (4-oxocyclohexyl)malonate and 16.1 g of benzylamine in 200 ml of methanol were reacted at 65° C. and 5 bar hydrogen pressure in the presence of 5 g of palladium/carbon catalyst (5%). The catalyst was filtered off and the mixture was concentrated. The cis/trans isomers were separated by silica gel chromatography (ethyl acetate/methanol 19:1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6](O)(=[O:9])[CH2:7][OH:8]>CC1C=CC=CC=1C>[OH:9][CH2:6][C:7]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: C1CCNC1
Reactant: O=C(O)CO
Solvent: Cc1ccccc1C
Product: O=C(CO)N1CCCC1
Yield: 89.9 %

Procedure:
Pyrrolidine (3.0 mL; 35.9 mmol) was added to glycolic acid (2.73 g; 35.9 mmol) over 5 minutes while cooling in an ice bath. The suspension was diluted with o-xylene (3.5 mL) and heated to reflux for 7 h whereupon the o-xylene was removed by distillation to afford the title compound (4.17 g; 90%) as an orange oil. 1H NMR (CDCl3) δ 1.86-1.92 (m, 2H), 1.96-2.02 (m, 2H), 3.26-3.29 (m, 2H), 3.52-3.55 (m, 3H), 4.08 (s, 2H); 13C NMR (CDCl3) δ 23.94, 25.74, 44.26, 45.96, 60.48, 169.90.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH2:17]Br)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[P:23]([O:32]C(C)C)([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH2:17][P:23]([O:28][CH:29]([CH3:31])[CH3:30])([O:24][CH:25]([CH3:27])[CH3:26])=[O:32])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)COCc1ccccc1)NC=O
Product: CCOC(=O)C(C=C(COCc1ccccc1)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 2 h

Procedure:
1.0 g (3.25 mmol) of 5-benzyloxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are suspended in 30 ml of 1,2-dichloroethane, and 0.38 ml (4.9 mmol) of thionyl chloride is added dropwise at room temperature. After 45 minutes, 20 ml of water are added to the yellow solution, and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed with saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated by evaporation. 5-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil which is reacted further in the crude state. 1.14 g (3.1 mmol) of 5-benzyloxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester and 10 ml (38.5 mmol) of triisopropyl phosphite (95%) are heated to 80° C. and stirred under a pressure of approximately 130 mbar for 31/2 hours. The excess triisopropyl phosphite is distilled off and the residue is purified by chromatography on silica gel with ethyl acetate. 5-benzyloxy-4-diisopropylphosphonomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH:17][CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCNCC(OCC)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-])OCC

Procedure:
4-Chloro-3,5-dinitrotoluene (4.32 grams; 0.02 mole), N-ethyl-N-(2,2-diethoxyethyl)amine (3.2 grams; 0.02 mole), triethylamine (2.02 grams; 0.02 mole) and toluene (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux overnight resulting in the formation of a precipitate. The reaction mixture was then filtered and the filtrate washed with water, dried and stripped of solvent to yield the desired product N-ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-p-toluidine.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[C:8]2[S:12][C:11](=[S:13])[N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2=[O:18])[O:4][N:3]=1.C(=O)([O-])O.[Na+]>O.[Pd]>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH:8]2[S:12][C:11](=[S:13])[N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2=[O:18])[O:4][N:3]=1
Reactant: Cc1cc(C=C2SC(=S)N(CC(=O)O)C2=O)on1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cc(CC2SC(=S)N(CC(=O)O)C2=O)on1
Yield: 29.8 %

Procedure:
In 100 ml of water were dissolved 2.0 g of 5-(3-methyl-5-isoxazolylmethylene)rhodanine-3-acetic acid and 1.0 g of sodium hydrogencarbonate. To the solution was added 1.0 g of 10% palladium charcoal and the mixture was subjected to a reduction at room temperature and under a hydrogen pressure of 3 atm. After completion of the reaction, the catalyst was removed by filtration. To the filtrate was added dilute hydrochloric acid to adjust the pH to 1. The precipitate was separated by filtration and recrystallized from water, giving 0.6 g of 5-(3-methyl-5-isoxazolylmethyl)rhodanine- 3-acetic acid (Compound 1 g) having a melting point of 235° to 240° C. (decomposition) in a yield of 30 %.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.C(N(C(C)C)CC)(C)C.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:39])[N:31]([CH3:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:10][C:2]([CH3:1])([CH2:3][C:4](=[O:5])[NH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30](=[O:39])[N:31]([CH3:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:27][CH:28]=1)[CH2:8][C:7]([OH:6])=[O:9]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCNC(=O)CC(C)(C)CC(=O)O)cc1)c1ccccc1
Yield: 95 %

Procedure:
A solution of 3,3-dimethylglutaric anhydride (0.3 mmol), diisopropylethylamine (0.30 mmol) and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol) in CH2Cl2 (3 mL) was stirred 1 h at rt. The mixture was washed with water and brine, dried and evaporated to give the title compound in 95% yield as an oil. HPLC-MS: m/z=413.2 (M+1); Rt=3.20 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([CH3:24])[CH:8]=1.C(N(CC)CC)C>N1C=CC=CC=1>[C:11]([C:10]1[C:9]([CH3:24])=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:13]=1)#[N:12]
Reactant: Cc1cc(N)c(Sc2ccc(F)cc2F)cc1C#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (2.2 ml) was added dropwise to an ice-cooled solution of 4-amino-5-(2,4-difluorophenylthio)-2-methylbenzonitrile (3.9 g) and triethylamine (3.9 ml) in pyridine (40 ml). The mixture was stirred overnight at room temperature and concentrated to dryness. To the residue were added pyridine (10 ml) and 5% aqueous solution of sodium hydroxide (50 ml). The resulting mixture was stirred for 2 hours and washed with toluene (50 ml). The aqueous layer was acidified with hydrochloric acid, and the precipitates obtained were recrystallized from a mixture of ethanol and ethyl acetate to give a pale brown powder of 4'-cyano-2'-(2,4-difluorophenylthio)-5'-methylmethanesulfonanilide (2.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)CC)C.C(Cl)Cl>>[C:18]([O:17][C:9]1[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][C:13](=[O:14])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC(=O)Cl
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)OC1=C(c2ccc(C)cc2)C(=O)CC(C)(C)C1
Yield: 71 %

Procedure:
Using the procedure described in Example III and starting with 3.00 g (0.0130 mol) of 2-(4'-methylphenyl)-5,5-dimethyl-1,3-cyclohexanedione, 1.59 g (0.0098 mol) of octanoyl chloride, 2.63 g (0.0260 mol) of triethylamine, and 30 mol of methylene chloride, 2.5 g (71% yield) of a clear, colorless oil was obtained as the desired product.
Reaction SMILES: F[C:2]1(C(C2C=CC=CC=2)=O)[CH:16]=[CH:15][C:5]([C:6](C2C=CC(F)=CC=2)=[O:7])=[CH:4][CH2:3]1.[Cl:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[O:31])=[CH:28][C:27]=1C(C1C=CC=CC=1)=O.FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1C(C1C=CC=CC=1)=O.[N+](C1C=C(C=CC=1F)C(C1C=CC(F)=C([N+]([O-])=O)C=1)=O)([O-])=O.[N+](C1C=C(C=CC=1Cl)C(C1C=CC(Cl)=C([N+]([O-])=O)C=1)=O)([O-])=O>>[Cl:25][C:26]1([C:6]([C:5]2[CH:15]=[CH:16][CH:2]=[CH:3][CH:4]=2)=[O:7])[CH:40]=[CH:39][C:29]([C:30]([C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:31])=[CH:28][CH2:27]1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)c(C(=O)c2ccccc2)c1
Reactant: O=C(C1=CCC(F)(C(=O)c2ccccc2)C=C1)c1ccc(F)cc1
Agent: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C(c1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(c1ccc(F)cc1)c1ccc(F)c(C(=O)c2ccccc2)c1
Product: O=C(C1=CCC(Cl)(C(=O)c2ccccc2)C=C1)c1ccc(Cl)cc1

Procedure:
##STR11## 4,4'-difluoroterephthalophenone: ##STR12## 4,4'-dichloro-isophthalophenone: ##STR13## 4,4'-difluoro-isophthalophenone: ##STR14## 4,4'-bis-(p-chlorobenzoyl)-diphenyl ether: ##STR15## 4,4'-bis-(p-fluorobenzoyl)-diphenyl ether: ##STR16## 3,3'-dinitro-4,4'-dichlorobenzophenone 3,3'-dinitro-4,4'-difluorobenzophenone
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:11]=1[F:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.CCCCCC.[C:31](=[O:33])=[O:32].Cl>C1COCC1>[CH2:1]([O:9][C:10]1[C:11]([F:19])=[C:12]([F:18])[C:13]([C:31]([OH:33])=[O:32])=[C:14]([F:17])[C:15]=1[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C=O
Reactant: CCCCCCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
33.4 g of the compound (8) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 90 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 21.4 g (66 mmol) of 4-octyloxy-2,3,5,6-tetrafluorobenzoic acid (9).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([Cl:30])=[CH:24][C:23]=2[Cl:31])=[C:5]2[S:11][C:10](/[CH:12]=[CH:13]/[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:9][C:6]2=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C:4]([NH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([Cl:30])=[CH:24][C:23]=2[Cl:31])=[C:5]2[S:11][C:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(/C=C/C(=O)OC(C)(C)C)sc23)c(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2c(C#N)cnc3cc(/C=C/C(=O)O)sc23)c(Cl)cc1Cl
Yield: 92.3 %

Procedure:
A solution of tert-butyl (2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2yl)prop-2-enoate (910.8 mg, 1.91 mmol), trifluoroacetic acid (2.18 g, 19.1 mmol) in 27 mL of dichloromethane is stirred at room temparature for 3 days, then concentrated in vacuo. The residue is triturated with ether to provide 741 mg of (2E)-3-(6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl)prop-2-enoic acid as a beige solid, mp >250° C.; 1H NMR (DMSO-d6) δ 3.84 (s, 3H), 6.28 (d, J=16 Hz, 1H), 7.38 (s, 1H), 7.70–7.88 (m, 2H), 7.90 (s, 1H), 8.62 (s, 1H), 9.81 (s, 1H), 12.50 (s, 1H); MS 420.1, 422.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:54][C:55]([F:66])([F:65])[C:56]1[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15]([C:59]4[CH:60]=[CH:61][C:56]([C:55]([F:66])([F:65])[F:54])=[CH:57][CH:58]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(C(F)(F)F)cc2)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 57 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-fluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 24 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 4-(trifluoromethyl)phenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=1:4) to obtain the title compound (57%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[C:20]([O:22][CH3:23])=[O:21])#[N:2].[OH-:24].[Na+].Cl>CO>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:24])[NH2:2]
Reactant: [OH-]
Reactant: COC(=O)c1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc3c(c2)COB3O)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A mixture of 5-(4-Cyano-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (5.25 g, 17.0 mmol) and 1 M NaOH (50 mL) in methanol (150 mL) was stirred at room temperature for 1 h. The mixture was acidified with 6 M HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate) followed by trituration with diisopropyl ether to give 5-(4-Carbamoyl-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (1.09 g, 19%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[O:30]=[C:11]1[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12]1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and pyridine-2-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.017 min, m/z=494.1; 1H NMR (CDCl3) 1.37-1.48 (m, 1H), 1.49 (d, 3H), 1.67 (m, 1H), 1.82-1.99 (m, 2H), 2.05-2.18 (m, 1H), 2.12-2.23 (m, 2H), 2.82 (m, 4H), 3.00 (m, 2H), 4.25 (m, 1H), 5.65 (m, 1H), 6.96 (d, 2H), 7.14-7.29 (m, 6H), 7.55 (d, 1H), 7.65 (m, 3H), 8.58 (d, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Br-:1].[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:5]=1)([OH:11])=[O:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Temperature: 115 °C
Yield: 94.7 %

Procedure:
10.7 g (50 mmole) of α-bromo-4-toluoic acid and 13.1 g (50 mmole) of triphenylphosphine were dissolved in 105 ml of toluene under a nitrogen atmosphere. The mixture was heated at 115° C. for 5 hours. After cooling, the mixture was filtered and dried in a vacuum-oven at 60° C. and 22.6 g of a white solid were obtained (yield 94.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:8][CH:7]([CH3:24])[C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:8][CH:7]([CH3:24])[C:6]1=[S:29]
Reactant: COC(=O)C(C)N1C(=O)C(C)N=C(c2ccccc2F)c2cc(Br)ccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)N1C(=S)C(C)N=C(c2ccccc2F)c2cc(Br)ccc21

Procedure:
A mixture of 0.01 mole of 7-bromo-3,α-dimethyl-5-(o-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-bromo-3,α-dimethyl-5-(o-fluorophenyl)-2,3-dihydro-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: C(N=C1C=CC=CC1O[CH:13]=[N:14][C:15]1[CH:16]=[C:17](/[C:21](/[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:18]=[CH:19][CH:20]=1)(=O)C1C=CC=CC=1.[CH3:40][CH:41]([CH3:44])[CH2:42][NH2:43].[OH-:45].[Na+]>C(O)(C)C>[C:42]([N:43]=[C:13]([NH:32][CH2:31][CH:30]([CH3:35])[CH3:21])[NH:14][C:15]1[CH:16]=[C:17](/[C:21](/[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=[CH:19][CH:20]=1)(=[O:45])[C:41]1[CH:44]=[CH:16][CH:15]=[CH:20][CH:40]=1
Reactant: [OH-]
Reactant: COC(=O)CCC/C=C(/c1cccnc1)c1cccc(N=COC2C=CC=CC2=NC(=O)c2ccccc2)c1
Reactant: CC(C)CN
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)CNC(=NC(=O)c1ccccc1)Nc1cccc(/C(=C\CCCC(=O)O)c2cccnc2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2.6 g methyl 5E-6-(3-(benzoylimino-phenoxymethyleneamino)phenyl)-6-(3-pyridyl)hex-5-enoate and 5 ml of 2-methylpropylamine are refluxed for 1 hour in 50 ml of isopropanol. The reaction mixture is cooled to 50° C., mixed with 15 ml of 1N sodium hydroxide solution and stirred for 30 minutes at this temperature. The solvent is removed, the residue is taken up in water and washed with ethyl acetate. The aqueous phase is adjusted to a pH value of 4-5 by the addition of citric acid, the precipitate formed is suction filtered and washed with water. The filter cake is recrystallised from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[NH:8])=[N:4][O:5][N:6]=1.Cl[CH2:15][C:16](=O)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([N:9]1[CH:15]=[C:16]([CH3:17])[N:8]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CNC(=N)c1nonc1N
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(CC(C)C)c(-c2nonc2N)n1
Yield: 5.6 %

Procedure:
A mixture of 4-amino-N-isobutyl-1,2,5-oxadiazole-3-carboxamidine (38 mg, 0.2 mmol), 1-chloropropanone (37 mg, 0.4 mmol) and potassium carbonate (55 mg, 0.4 mmol) in DMF (0.5 mL) was microwaved for 20 minutes at 180° C. The crude mixture was purified via Gilson and then a flash pipette column to afford the title compound as a white solid 2.5 mg. HPLC Rt 5.6 min; MS 222.1 as M+1 peak; HPLC Method B Rt 3.4 min. 1HNMR (CDCl3) 6.94 (s, 1H); 5.73 (br, 2H); 4.15 (d, 2H); 2.3 (s, 3H); 2.15 (m, 1H); 0.95 (d, 6H).
Reaction SMILES: O=C1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]1=[CH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].[C:22](=[O:25])([O-])[O-:23].[Na+].[Na+].[CH3:28]O>>[C:5]([NH:4][C:3](=[CH:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:16]([C:17]#[N:18])[CH:15]=1)[C:22]([O:23][CH3:28])=[O:25])(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO
Reactant: N#Cc1cccc(C=C2N=C(c3ccccc3)OC2=O)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C(=Cc1cccc(C#N)c1)NC(=O)c1ccccc1
Yield: 74 %

Procedure:
A suspension of 3-[(5-oxo-2-phenyl-1,3-oxazol-4(5H)-ylidene)-methyl]benzonitrile (1.98 g, 9.01 mmol) and sodium carbonate (26 mg, 0.25 mmol) in methanol was heated under reflux for 2.5 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue to separate the organic layer. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and concentrated under reduced pressure. The residue was applied to silica gel column chromatography (gradient elution with hexane-ethyl acetate from 80:20 to 33:67) and recrystallized from acetone-diisopropyl ether to give the title compound (1.63 g, 74%).
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:8]([C:10]1([C:16]2[N:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)#[N:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([C:10]1([C:16]2[N:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[CH:26]=[N:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=4)[C:29]=3[CH3:30])=[O:24])=[CH:18][CH:17]=2)[CH2:11][CH2:12][N:13]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:14][CH2:15]1)#[N:9]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(S(=O)(=O)C(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Isopropylsulfonyl chloride (72 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (227 mg) described in Reference Example 169 and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml) and stirred at room temperature for six hours. Then, potassium carbonate (276 mg) and isopropylsulfonyl chloride (144 μl) were added and stirred at room temperature for 0.5 hours. Water was added to the reaction solution and the precipitated solid was washed with water, ethanol and ethyl acetate to give the titled compound (151 mg) as a white solid.