Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.N1C=CC=CC=1.[CH3:23][C:24]1[C:25](B(O)O)=[N:26][CH:27]=[CH:28][CH:29]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][C:25]2[C:24]([CH3:23])=[CH:29][CH:28]=[CH:27][N:26]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: Cc1cccnc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)c(Oc3ncccc3C)c2CC[C@@H]1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
A 100-mL, round-bottom flask equipped with a balloon filled with air was charged with (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.200 g, 0.70 mmol), pyridine (1 mL), copper (II) acetate (0.382 g, 2.10 mmol), 3-methylpyridin-2-ylboronic acid 0.190 g, 1.39 mmol) and N,N-dimethylformamide (8 mL). The resulting mixture stirred at 90° C. overnight. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1:8, ethyl acetate/petroleum ether) to afford (S)-1-(6-bromo-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.129 g, 49%) as yellow oil. MS (ESI, pos. ion) m/z 375, 377 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Cl.[CH3:27][O:28][C:29]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][NH:35][CH2:34]2)=[O:30].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:27][O:28][C:29]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][N:35]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:34]2)=[O:30]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 20 %

Procedure:
180 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 52 mg of the target compound.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([O:17][C:18](=[O:35])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])([CH3:16])[CH3:15]>C(O)C>[CH3:13][C:14]([O:17][C:18](=[O:35])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][P:27]([O:29][CH2:30][CH3:31])([O:32][CH2:33][CH3:34])=[O:28])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:15])[CH3:16]
Reactant: CCOP(=O)(CCNCCCCNC(=O)OC(C)(C)C)OCC
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(N(CCCCNC(=O)OC(C)(C)C)CCP(=O)(OCC)OCC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.8 mL, 39 mmol) in absolute ethanol (200 mL) prepared under nitrogen, was added a solution of [4-[[2-(diethoxyphosphinyl)ethyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester (13.7 g, 39 mmol) in ethanol (75 mL) over 1.75 hour. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in chloroform (150 mL), preadsorbed onto silica gel, and purified by flash chromatography (9 cm diameter, elution with 2.5% methanol in dichloromethane) to yield [4-[[2-(diethoxyphosphinyl)ethyl](2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]-butyl]carbamic acid 1,1-dimethylethyl ester as a yellow viscous oil (16.8 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(/C=C/c2ccc(F)cc2)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(/C=C/c3ccc(F)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of (E)-4-[2-(4-fluoro-phenyl)-vinyl]-phenylamine with itaconic acid yields the (RS)-(E)-1-{4-[2-(4-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid which was directly engaged in the next step without further purification and characterisation.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([C:45]([CH3:47])=[CH2:46])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H][H]>[Pd].CO>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42][CH3:43])=[O:41])=[CH:36][C:35]=5[CH3:44])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[CH:24][CH:23]=[C:22]([CH:45]([CH3:47])[CH3:46])[N:21]=3)[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: [H][H]
Reactant: C=C(C)c1ccc(-c2cc(-c3ccc(C(=O)OC)cc3C)ccc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(C)C)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
Methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropenylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (131 mg, 0.189 mmol) and a catalytic amount of palladium on carbon and CH3OH (5 mL) were stirred vigorously under a balloon atmosphere of hydrogen for 1 h and 20 min at 20° C. The reaction mixture was filtered then the filtrate was concentrated in vacuo to afford methyl 3′-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropylpyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate, as a light yellow glass. LCMS calc.=700.24; found=701.29 (M+1).
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[O-]CC.[Na+].Br[CH:16]([CH3:20])[C:17](=[O:19])[CH3:18]>C(O)C>[CH2:9]([O:8][C:2]([CH:3]([CH:16]([CH3:20])[C:17](=[O:19])[CH3:18])[C:4](=[O:5])[CH3:6])=[O:7])[CH3:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)C(C)Br
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)C(C)C(C)=O
Reaction time: 0.5 h

Procedure:
7.3 G., 0.317 mol of sodium was dissolved in 125 ml. of absolute ethanol. 87.0 G. (0.669 mol) of ethyl acetoacetate were added to the resulting solution of sodium ethoxide in the cold. The reaction mixture was heated to reflux and 48.6 g. (0.322 mol) of freshly distilled 3-bromo-2-butanone were added dropwise with stirring over a period of 30 min. Refluxing was continued until the mixture tested neutral to pH paper (~1.5 hrs.). The precipitated sodium bromide was filtered off the cold solution and most of the ethanol was removed on an evaporator. The mixture was filtered again and distilled. The 3-ethoxycarbonyl-4-methylhexane-2,4-dione fraction which boiled at 131°-137° C./18 mm. was collected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:30])[N:9]3[CH2:13][C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)(O)[C:11]=1[C:10]=23.C(N(S(F)(F)[F:37])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:30])[N:9]3[CH2:13][C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)([F:37])[C:11]=1[C:10]=23
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CC2(F)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Yield: 33.4 %

Procedure:
A solution of 1,1-dimethylethyl {1-[(3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (15.93 g, 38.1 mmol) in dichloromethane (320 ml) was cooled in an ice bath and treated with (diethylamino)sulphur trifluoride (10.1 ml, 75.9 mmol). After 2.5 hours at room temperature saturated aqueous sodium bicarbonate solution was added, then the phases separated. The aqueous phase was extracted twice more with dichloromethane and the combined organic extracts combined and evaporated. Chromatography eluting with a methanol in dichloromethane gradient afforded the product (5.35 g, 33%).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8]/[N:9]=[C:10]2/[C:11]([CH3:26])=[N:12][N:13]([C:16]3[CH:25]=[CH:24][C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=3)[C:14]/2=[O:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:27]1[O:31][C:30]([C:32]([OH:34])=[O:33])=[CH:29][CH:28]=1.[OH-].[Na+:36]>O1CCCC1>[Na+:36].[Na+:36].[OH:1][C:2]1[C:7]([NH:8]/[N:9]=[C:10]2/[C:11]([CH3:26])=[N:12][N:13]([C:16]3[CH:25]=[CH:24][C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=3)[C:14]/2=[O:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:27]1[O:31][C:30]([C:32]([O-:34])=[O:33])=[CH:29][CH:28]=1.[OH:1][C:2]1[C:7]([NH:8]/[N:9]=[C:10]2/[C:11]([CH3:26])=[N:12][N:13]([C:16]3[CH:25]=[CH:24][C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=3)[C:14]/2=[O:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:27]1[O:31][C:30]([C:32]([O-:34])=[O:33])=[CH:29][CH:28]=1
Reactant: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)/C1=N\Nc1cccc(-c2ccc(C(=O)O)o2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)/C1=N\Nc1cccc(-c2ccc(C(=O)[O-])o2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
(Z)-5-(2-hydroxy-3-{N′-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-phenyl)-furan-2-carboxylic acid 7d (110 mg, 0.24 mmol) was dissolved in 4 mL of tetrahydrofuran to form a dark red suspension. The reaction mixture was added dropwise with 1 M sodium hydroxide solution (0.4 mL, 0.44 mmol), stirred for 2 hours at room temperature. The reaction mixture was filtered, then the filtrate was added with 4 mL methanol and concentrated under reduced pressure. The resulting solid was washed with hexane to obtain the title compound (Z)-5-(2-hydroxy-3-{N′-[3-methyl-5-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-phenyl)-furan-2-carboxylic acid disodium salt 14 (115 mg, yield: 81.8%) as a dark solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:10]1([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCC1
Reactant: COc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(NC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A solution of p-anisidine (615 mg), cyclopentanone (420 mg) and acetic acid (2 ml) in methanol (30 ml) was cooled to 0° C., and sodium cyanoborohydride (315 mg) was added portionwise. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was then basified with 1N aqueous sodium hydroxide, and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (SiO2 30 g, diethyl ether:n-hexane=1:3) to give N-cyclopentyl-p-anisidine (530 mg).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]3[CH:9]=[CH:10][C:11](O)=[N:12][CH:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.P(Cl)(Cl)([Cl:17])=O.[OH-].[Na+]>>[Cl:17][C:11]1[N:12]=[CH:13][C:8]([C:4]23[CH2:7][N:1]([CH2:6][CH2:5]2)[CH2:2][CH2:3]3)=[CH:9][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(C23CCN(CC2)C3)cn1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(C23CCN(CC2)C3)cn1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
0.37 g (1.94 mmol) of 5-(1-azabicyclo[2.2.1]hept-4-yl)pyridin-2-ol obtained in Example 4, in solution in 5.44 ml (58.35 mmol) of phosphorus oxychloride, is introduced into a sealed tube and the combined mixture is subsequently stirred at 140° C. for 45 minutes. The reaction mixture is subsequently brought back to ambient temperature, poured onto 200 g of crushed ice and stirred for 15 minutes. The medium is then very slowly adjusted to pH 10 with a concentrated sodium hydroxide solution. The combined mixture is subsequently extracted twice with chloroform and the organic phases are subsequently combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 370 mg of the desired compound in the form of a brown powder.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH2:36])=[N:35][C:30]2=[CH:29][CH:28]=1)[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:36][C:34]3[S:33][C:31]4[C:30]([N:35]=3)=[CH:29][CH:28]=[C:27]([O:26][CH2:24][CH3:25])[N:32]=4)=[O:16])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOc1ccc2nc(N)sc2n1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 37.1 %

Procedure:
The compound of example A81 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.25 g, 0.73 mmol), 5-ethoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.157 g, 0.80 mmol), HOBt (0.148 g, 1.10 mmol), and EDCI (0.210 g, 1.10 mmol), N-methyl morpholine (0.22, 2.20 mmol) in DMF (5 mL) to provide the title compound (0.140 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[F:12])=[O:9]
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)c1cc(Cl)ccc1O
Yield: 77.9 %

Procedure:
Using 5-chlorosalicylic acid and 2-fluoro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[O:6][C:7]([C:9]1[C:13]([NH:14][C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:21][CH:20]=[C:19]([CH:30]3[CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=1)=O>>[CH:1]1([NH:4][C:7]([C:9]2[C:13]([NH:14][C:15]([C:17]3[C:22]([NH:23][C:24]4[CH:25]=[N:26][CH:27]=[N:28][CH:29]=4)=[CH:21][CH:20]=[C:19]([CH:30]4[CH2:32][CH2:31]4)[N:18]=3)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NC2CC2)n1
Yield: 24 %

Procedure:
According to the general method described in step 5 of example 27, reaction of cyclopropylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (24%) as amorphous yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[BrH:33].[S:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][N:37]3[CH2:36][CH2:35][S:34][CH2:39][CH2:38]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Reactant: O=C(O)CCCN1CCSCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCSCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C

Procedure:
Equimolar amounts of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, γ-thiomorpholinobutyric acid hydrobromide and dicyclohexylcarbodiimide are reacted to form the desired product.
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]([C:26](O)=[O:27])#[C:22][C:23]([OH:25])=[O:24]>>[CH2:1]([N:7]1[C:26](=[O:27])[C:21](=[CH:22][C:23]([OH:25])=[O:24])[S:9][C:8]1=[N:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=S)Nc1cccc2ccccc12
Reactant: O=C(O)C#CC(=O)O
Product: CCCCCCN1C(=O)C(=CC(=O)O)SC1=Nc1cccc2ccccc12
Yield: 66.3 %

Procedure:
Prepared by the method described in Example 16 from N-hexyl-N'-1-naphthalenylthiourea (8.0 g, 28 mmoles) and acetylenedicarboxylic acid (3.4 g, 28 mmoles). Recrystallization from acetonitrile gave the product (7.1 g), mp 144°-145° C.
Reaction SMILES: [Na].Cl.[CH3:3][O:4][CH2:5][C:6]([NH2:8])=[NH:7].[CH:9]([CH:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12](OCC)=O)=[O:10]>C(O)C>[CH3:3][O:4][CH2:5][C:6]1[N:8]=[C:9]([OH:10])[C:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:7]=1
Reactant: COCC(=N)N
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cc1cnc(COC)nc1O
Temperature: 25 °C
Yield: 43 %

Procedure:
Sodium metal (0.754 mol) was dissolved in absolute ethanol (100 ml) and the resulting solution was added dropwise to a solution of methoxyacetamidine hydrochloride (0.703 mol) in ethanol (100 ml). After 15 minutes the reaction mixture was filtered and the filtrate was added to a solution of diethyl formylsuccinate (0.703 mol), which was prepared according to H. Nakao et al. Ann. Sankyo Res. Lab., 18, 33-37 (1966). The reaction was refluxed for 15 hours, cooled to room temperature and was then concentrated to obtain a crude solid. This solid was crystallized from isopropanol to obtain the title compound (43% yield), m.p. 142°-143° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][NH2:8])[CH:4]=[N:3][CH:2]=1.C[Al](C)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([C:36]([F:39])([F:38])[F:37])/[CH:22]=[CH:23]/[C:24]2[CH:34]=[CH:33][C:27]([C:28](OCC)=[O:29])=[C:26]([CH3:35])[CH:25]=2)[CH:17]=[C:18]([Cl:20])[CH:19]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([C:36]([F:39])([F:37])[F:38])/[CH:22]=[CH:23]/[C:24]2[CH:34]=[CH:33][C:27]([C:28]([NH:8][CH2:7][C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[O:29])=[C:26]([CH3:35])[CH:25]=2)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CCOC(=O)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Reactant: NCc1cncnc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1cncnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a stirred solution of (pyrimidin-5-yl)methanamine (0.15 g, 1.43 mmol) in CH2Cl2 (10 mL) was added drop wise trimethylaluminum (2 M solution in toluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at 25° C. for 30 min. A solution of ethyl 4-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (0.3 g, 0.71 mmol) in CH2Cl2 was added drop wise to the reaction mixture at 25° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound (0.18 g, 55%): mp 141-144° C.; 1H (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.40 (dd, J=16.0, 7.6 Hz 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H); ESIMS m/z 477.83 ([M−H]−).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][C@@H:16]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>C(Cl)Cl>[Cl:34][C:28]1[CH:27]=[C:26]([NH:25][C@H:16]([CH2:15][NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:31]=[CH:30][C:29]=1[C:32]#[N:33]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (14.15 g, 64 mmol) in CH2Cl2 (50 mL) was added dropwise over 20 min to an ice cold solution of 1,1-dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (19.8 g, 64 mmol) and Et3N (6.5 g, 64 mmol) in CH2Cl2 (150 mL) and the reaction was stirred at room temperature for 30 min. The reaction was washed with H2O and cold 0.1 N HCl. The organic layer was dried over CaCl2, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH:7]=[C:8]([OH:10])[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:53])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)[C:34]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:26]>CC(C)=O.CN(C=O)C>[CH2:25]([O:27][C:28](=[O:53])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:10][C:8]2[CH:7]=[C:6]([O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=2)[C:34]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:26]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CC(=O)c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OS(=O)(=O)C(F)(F)F)cc(C(C)=O)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-acetyl-5-hydroxy-phenyl ester (1.0 g) in a mixture of acetone and DMF (2:1, 80 mL) were added potassium carbonate (2.4 g) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.8 g). The resulting mixture was stirred at 75° C. for 3 h. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 1.7 g of the title compound (72% yield). HRMS calcd for C32H41O10S1F3 [M+H]+ 675.2446, observed 675.2440.