Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:61]C1C=CC(N=C=S)=CC=1>>[Cl:61][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)cc2C1=O

Procedure:
The compound of example 61 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 4-chlorophenyl isothiocyanate. The compound of example 61 was used directly without isolation for the preparation of compound of example 62.
Reaction SMILES: C[N:2]1[C:8](=O)[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[C:14]([NH:21][CH2:22][CH2:23][NH2:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14](=[O:15])[NH:21][CH2:22][CH2:23][NH:24][C:5](=[O:7])[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[NH:2][CH3:8])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Product: CNc1ccccc1C(=O)NCCNC(=O)OC(C)(C)C

Procedure:
Starting from N-methylisatoic anhydride and N-Boc-ethylenediamine and using Procedure S, the title compound was obtained as a slightly brown solid (903 mg; quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([S:11]([F:14])(=[O:13])=[O:12])=[CH2:10]>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]=[CH:9][S:11]([F:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: C=CS(=O)(=O)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC=CS(=O)(=O)F)cc1
Yield: 34.7 %

Procedure:
The reaction between 4-methylaniline (1.61 g, 15 mmol) and ethenesulfonyl fluoride (2.18 g, 19 mmol) was carried out in DMF (30 mL) at ambient temperature for 2.5 hours as described in Example 16. There was obtained a tan residue which was crystallized from ether/hexane to afford the title compound as a tan solid (1.12 g 34% yield), mp 61°-65° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:27]([F:29])[F:28])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.C[O:32][C:33](=[O:60])[CH2:34][O:35][C:36]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]2[C:37]=1[C:38]([CH3:59])=[C:39]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=1)[C:40]([O:47][CH:48]([F:50])[F:49])=[N:41]2.[OH-].[Li+].Cl>O.CO>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[C:8]2[O:26][CH:27]([F:29])[F:28].[Cl:46][C:43]1[CH:44]=[CH:45][C:36]([O:35][CH2:34][C:33]([OH:60])=[O:32])=[C:37]2[C:42]=1[N:41]=[C:40]([O:47][CH:48]([F:49])[F:50])[C:39]([CH2:51][C:52]1[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=1)=[C:38]2[CH3:59]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(F)cc3)c(C)c12
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(F)cc3)c(OC(F)F)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(Cc2ccc(F)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(F)cc1

Procedure:
A solution of [8-chloro-4-difluoromethoxy-3-(4-fluorobenzyl)-2-methylquinolin-5-yloxy]acetic acid methyl ester and [8-chloro-2-difluoromethoxy-3-(4-fluorobenzyl)-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.26 g), methanol (5.0 mL), water (3.0 mL) and lithium hydroxide solution (0.13 g mL) was stirred at room temperature for 1 hour. The solution was acidified by the addition of hydrochloric acid, extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile—(in water to afford [8-chloro-4-difluoromethoxy-3-(4-fluorobenzyl)-2-methylquinolin-5-yloxy]acetic acid as a white solid, 0.032 g and [8-chloro-2-difluoromethoxy-3-(4-fluorobenzyl)-4-methylquinolin-5-yloxy]acetic acid as a white solid, 0.029 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:20]1([S:26]([N:8]2[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1nc(-c2ccncc2)nc1-c1ccncc1

Procedure:
To 1.06 g. (0.005 mole) of 3,5-di(4-pyridyl)-1,2,4-triazole in 100 ml. of tetrahydrofuran is added 57% sodium hydride in mineral oil (0.21 g., 0.005 mole). The reaction mixture is heated at reflux for 1/2 hour, cooled and a solution of benzenesulfonyl chloride (0.88 g., 0.005 mole) is added. The reaction mixture is heated at reflux for 1/2 hour, cooled, filtered and concentrated to a solid. After recrystallization from acetonitrile 0.4 g. of 1-benzenesulfonyl-3,5-di(4-pyridyl)-1,2,4-triazole melting at 210°-212° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH2:20]F)=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([CH3:20])=[CH:15][N:14]=2)[CH:7]=1
Reactant: Nc1nc(Cl)ncc1CF
Reactant: OB(O)c1cc(Cl)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cnc(-c2cc(Cl)ccc2F)nc1N

Procedure:
trans-Dichlorobis(triphenylphosphine)palladium (II) (1.179 g, 1.680 mmol), 5-chloro-2-fluorophenylboronic acid (6.1 g, 35.3 mmol), 2-chloro-5-fluoromethylpyrimidin-4-amine (2.411 g, 16.80 mmol), 2M Na2CO3 (8.40 mL, 16.80 mmol) were combined in dioxane (79 mL) and refluxed for 1 hour. The reaction was cooled, concentrated and the solids were suspended in brine (50 mL) and then extracted with EtOAc (20 mL). The layers were separated, the organics were dried over Na2SO4, filtered and concentrated to give a residue which was passed through a silica plug (12 g) to give 2-(5-chloro-2-fluorophenyl)-5-methylpyrimidin-4-amine which was without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (3H, d, J=0.76 Hz) 6.85 (2H, br. s.) 7.31 (1H, dd, J=10.61, 8.84 Hz) 7.46-7.55 (1H, m) 7.88 (1H, dd, J=6.57, 3.03 Hz) 8.06 (1H, d, J=0.76 Hz). ESI-MS: m/z 238.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].O.[CH2:16]([N:19]([CH2:25][CH:26]=O)[C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH:17]=[CH2:18]>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:18][CH:17]2[CH:26]1[CH2:25][N:19]([C:20]([O:21][CH2:22][CH3:23])=[O:24])[CH2:16]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC2CN(C(=O)OCC)CC2N1Cc1ccccc1

Procedure:
50 g (0.25 mol) of N-benzylglycine ethyl ester in 1 l of toluene are heated under reflux in a water separator and 43 g (0.25 mol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are added dropwise during the course of two hours. The mixture is heated under reflux until water no longer separates and concentrated, and the residue is distilled.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[S:16][C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[S:55]1[C:59]([CH2:60][NH2:61])=[CH:58][C:57]2[CH:62]=[CH:63][CH:64]=[CH:65][C:56]1=2>CN(C)C=O>[S:55]1[C:59]([CH2:60][NH:61][C:21]([C:17]2[S:16][C:15]([N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]3=[O:24])=[N:19][C:18]=2[CH3:20])=[O:22])=[CH:58][C:57]2[CH:62]=[CH:63][CH:64]=[CH:65][C:56]1=2
Reactant: NCc1cc2ccccc2s1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cc2ccccc2s1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid (0.20 g, 0.58 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (0.27 g, 2.10 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.18 g, 0.93 mmol). The mixture was stirred for 30 minutes, followed by the addition of 1-hydroxybenzotriazole (0.11 g, 0.81 mmol) and benzo[b]thiophen-2-ylmethanamine (0.14 mL, 0.87 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (2×5 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexane. The title compound was obtained as a colorless solid in 78% yield (0.22 g): 1H NMR (300 MHz, DMSO-d6) δ 8.98 (t, J=5.8 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.82-7.85 (m, 1H), 7.76-7.73 (m, 1H), 7.51-7.23 (m, 8H), 6.34 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.65-4.63 (m, 2H), 2.56 (s, 3H); MS (ES+) m/z 488.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][S:31][CH3:32])[C:23]4=[O:33])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.CO.[OH:36]OS([O-])=O.[K+]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:36])[C:23]4=[O:33])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CSCCOc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)CCOc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Example 48 in a 2:1 mixture of methanol and water was added 1.0 equivalent of oxone. The mixture was stirred at room temperature for 10 min and directly subjected to reverse phase HPLC to isolate the title compound as a white powder after lyophilization. MS found for C22H20ClN5O4S2 (M+H)+ 518.1, 520.1 (Cl pattern).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].N[C:14]1C=NC=C[CH:19]=1.C(N)/C=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:12]([NH:8][C:1]([NH:3][C:7]1[CH:6]=[N:5][CH:4]=[CH:14][CH:19]=1)=[O:2])/[CH:11]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC/C=C/c1ccccc1
Reactant: Nc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NC/C=C/c1ccccc1)Nc1cccnc1
Temperature: 25 °C
Yield: 233.3 %

Procedure:
To 50 ml of a tetrahydrofuran solution containing 16.2 g of carbonyldiimidazole, a solution of 9.4 g of 3-aminopyridine dissolved in 50 ml of tetrahydrofuran was added dropwise under ice-cooling over 5 minutes. After stirring under ice-cooling for 30 minutes and at room temperature for 1 hour, the mixture was again ice-cooled, and 1.33 g of (E)-cinnamylamine was added, followed by stirring at room temperature for 18 hours. After distilling the solvent off, the residue was dissolved in ethyl acetate, washed with water and dried, followed by distillation of the solvent. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol=20:1) to give 5.9 g of (E)-N-cinnamyl-N'-(3-pyridyl) urea as colorless caramel.
Reaction SMILES: N[C:2]1C=NC=N[CH:7]=1.C(=O)C.[H][H].[CH2:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1)[CH3:14]>C(O)C.O=[Pt]=O>[CH2:13]([N:15]([C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1)[CH2:2][CH3:7])[CH3:14]
Reactant: CCNc1cncnc1
Reactant: [H][H]
Reactant: Nc1cncnc1
Agent: O=[Pt]=O
Agent: CC=O
Solvent: CCO
Product: CCN(CC)c1cncnc1

Procedure:
A suspension of the 5-aminopyrimidine, and one twenty-fifth an equal mass of PtO2, and 5 equivalents equivalents of aqueous acetaldehyde, in ethanol solvent, was shaken under 60 psi hydrogen gas for 24 h. At this time, TLC of an evaporated aliquot of the reaction mixture indicated complete conversion of the 5-(N-ethyl)aminopyrimidine. The Pt catalyst was removed by filtering the reaction mixture through Celite, and the 5-(N,N-diethyl)aminopyrimidine was isolated by evaporation of the ethanol solvent. The crude product was purified by flash chromatography on silica using EtOAc/hexanes.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@H:4]([CH:5]=C(C)C)[C@H:3]1[C:9]([O:11][CH2:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([CH3:21])=[C:15]([F:22])[C:14]=1[F:23])=[O:10].CO.O=O.[O:29]=[O+][O-]>O.C(OCC)(=O)C>[CH:5]([C@@H:4]1[C@@H:3]([C:9]([O:11][CH2:12][C:13]2[C:18]([F:19])=[C:17]([F:20])[C:16]([CH3:21])=[C:15]([F:22])[C:14]=2[F:23])=[O:10])[C:2]1([CH3:24])[CH3:1])=[O:29]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Reactant: O=[O+][O-]
Agent: O=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=O)C2(C)C)c(F)c1F
Temperature: -78 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A mixture of 1.27 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate, 20 ml of methanol and 20 ml of ethyl acetate was cooled to -78° C. Oxygen-containing ozone was bubbled into the mixture while stirring until the reaction mixture was colored blue. Then, nitrogen gas was bubbled into the blue reaction mixture to remove the excess ozone. Thereafter, 5 ml of dimethyl sulfide was added thereto. The resulting mixture was heated to room temperature. The reaction mixture, after having been allowed to stand for one day, was concentrated under reduced pressure. 20 Milliliters of acetone, 2 ml of water and 0.2 g of p-toluenesulfonic acid monohydrate were added to the resultant residue. The resulting reaction mixture, after having been allowed to stand at room temperature for 2 hours, was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to obtain 0.98 g (yield: 82%) of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-3-formyl-2,2-dimethyl-cyclopropanecarboxylate, m.p. 43.2° C.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].O=[Al-:15]=O.[Na+]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Al+3:15]
Reactant: O=[Al-]=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [Al+3]

Procedure:
To the amine in the sodium aluminate example above, citric acid was added to bring the pH to the range of 7.5-9. The control did not require any acid addition.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:6]=1)C.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:36][N:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:4](=[O:3])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[CH:6]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CNCCCCCCCCc1ccccc1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
N-methyl-N-(8-phenyloctyl)-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.238 g; 67%) from 3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ 7.94 (s, 2H); 7.84 (d, 2H); 7.68–7.56 (m, 4H); 7.44 (s, 2H); 7.30–7.12 (m, 5H); 3.24 (t, 2H); 3.52 and 3.33 (2bt, 2H); 3.40 (t, 2H); 3.08 (2s, 3H); 2.58 (bt, 2H); 1.60 (m, 4H); 1.42–1.12 (m, 8H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH:18]=[C:17]([CH2:20][C:21](=[O:38])[N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:39]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[NH2:39][C@@H:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][N:16]=2)[C:17]([CH2:20][C:21]([N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:26][CH2:27]2)=[O:38])=[CH:18][CH2:19][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2C(CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)=CC[C@H]1c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: N[C@@H]1c2nccnc2C(CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)=CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a 50 mL round-bottomed flask was dissolved tert-butyl (5S,6S)-6-(2,3-difluorophenyl)-9-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl)ethyl)-6,7-dihydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (58.6 mg, 0.093 mmol) in methylene chloride (1 mL). trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at rt for 1 h. LCMS showed complete conversion. Volatile components were removed in vacuo, and the residue was partitioned between ethyl acetate/0.5N sodium hydroxide/saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried and concentrated to give a tan oil. flash column chromatography up to 10% methanol (2M ammonia) in methylene chloride afforded the desired product (36 mg, 73%) as a tan solid: MS (ESI)[M+H+]=532.3; 1H NMR (400 MHz, CDCl3) δ 8.47 (ddd, J=11.4, 8.1, 2.5 Hz, 2H), 8.07 (d, J=5.1 Hz, 1H), 7.46 (t, J=6.7 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.20 (d, J=7.1 Hz, 1H), 7.08 (dt, J=14.8, 7.7 Hz, 2H), 6.99 (td, J=8.2, 5.3 Hz, 2H), 6.41 (dt, J=22.6, 7.2 Hz, 1H), 4.90-4.68 (m, 2H), 4.56 (dd, J=17.3, 12.7 Hz, 1H), 4.15 (ddd, J=24.9, 20.2, 15.2 Hz, 2H), 3.83 (dt, J=7.2, 6.4 Hz, 1H), 3.64 (dd, J=33.2, 16.2 Hz, 1H), 3.26 (t, J=13.1 Hz, 1H), 2.69 (dd, J=28.5, 13.4 Hz, 1H), 2.39 (d, J=6.8 Hz, 2H), 2.33-2.05 (m, 3H), 2.03-1.69 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −137.26-−138.00 (m), −142.22 (dd, J=96.1, 21.6 Hz).
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.C.[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=[CH:23][N:22]=1.C1COCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][O:30][C:2]2[C:3]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]3[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Reactant: CN(C)CCOc1ncccc1OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Temperature: 100 °C
Reaction time: 0.42 h

Procedure:
(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (20 L in toluene solution; see Example 8 for preparation) and active charcoal (201 g) was added to the 328 L-reactor containing 2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethanol (Example 1C) in toluene solution. The mixture was stirred for 25 minutes before transferred to a through a GAF-filter (containing a Teflon filter bag) to a 250 L-stainless steel reactor. The mixture was heated to 100° C. before the prepared “THF/potassium tert-butoxide—solution” was added to the reactor using a 50 L addition bowl. After 10 L “THF/potassium tert-butoxide—solution” was added, an IP-HPLC was taken to ensure that the title compound had started to form. The total addition of THF/potassium tert-butoxide-solution was made during 2 h and 15 minutes. Water (21 L) and sodium chloride (1 kg) was added to a 198 L-glasslined reactor. The salt was dissolved before the reaction mixture was transferred from the 328 L-reactor and quenched into the 198 L-reactor. Toluene (10 L) was also transferred to make sure that no reaction-mixture was left in the hoses used for the transfer. The mixture was then heated to 70° C. before the mechanical stirrer was turned off. The phases were allowed to separate for 30 minutes before the water phase (25 L) was discharged. The mixture was heated to reflux and toluene (10 L) was distilled off. Water (100 L) was added and the mixture was heated to reflux again and 60 L of water was distilled off. The remaining solution was then cooled to RT. The title compound was never isolated; it was directly used in the next step (Example 3C).
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[C:11]1([CH2:17][O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])=[CH:24][C:20]=2[C:21](O)=[O:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=C(N)C=1.C(Cl)CCl>CN(C)C=O.O>[C:11]1([CH2:17][O:18][C:19]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])=[CH:24][C:20]=2[C:21]([NH:7][C:5]2[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=2)=[O:22])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: Nc1cccnc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Neat HOBT (90 mg, 0.59 mmol) was added in one charge to a stirred solution of 2-[(phenylmethyl)oxy]-5-(1-piperidinylcarbonyl)benzoic acid (may be prepared as described in Description 53; 200 mg, 0.59 mmol), 3-pyridinamine (55.5 mg, 0.59 mmol), and EDC (113 mg, 0.59 mmol) in N,N-dimethylformamide (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water (50 ml). The precipitate was collected by filtration, washed with ether (5 ml), and dried to yield the title compound as a white solid. 65 mg.