Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: COC(=O)c1ccc(C)c(N)c1C
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2C)c1C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (2.0 g, 0.0093 mol) in CH2Cl2 (20 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (1.49 g, 0.0084 mol, see preparation 10) and N,N-diisopropylethylamine (4.79 g, 0.0372 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 8.87 g, 0.028 mol) is added via syringe and stirred at 50° C. After 16 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted twice with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 10% ethyl acetate in hexane to give the title compound as a white solid (2.80 g, 80%). Mass spectrum (m/z): 376.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].N[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:14]=1.O.CCOC(C)=O.[N:38]1C=CC=CC=1>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][O:20][C:15]2[CH:14]=[C:13]([C:7]3[C:2]([Cl:1])=[C:3]([S:8]([NH2:38])(=[O:10])=[O:9])[CH:4]=[CH:5][CH:6]=3)[CH:18]=[C:17]([CH3:19])[CH:16]=2)=[CH:28][CH:27]=1)#[N:30]
Reactant: c1ccncc1
Reactant: Cc1cc(N)cc(OCCc2ccc(C#N)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(OCCc2ccc(C#N)cc2)cc(-c2cccc(S(N)(=O)=O)c2Cl)c1
Reaction time: 4 h
Yield: 78 %

Procedure:
2-Chlorophenylsulfonyl chloride (0.152 g; 0.72 mmol) was added to a cooled solution (ice:water temperature) of amino-3-[2-(4-cyanophenyl)ethoxy]-5-methylbenzene (0.16 g; 0.60 mmol; from Example 17(iii) above) in pyridine (5 mL), and the resultant orange solution was stirred for 4 hours. Addition of H2O (30 mL), extraction with EtOAc, drying (MgSO4), evaporation of the solvent, and purification by flash chromatography (SiO2; 25-33% EtOAc:hexane) yielded 0.20 g (78%) of the sub-title compound.
Reaction SMILES: Cl[C:2]1[N:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:18]=[C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)[CH:20]=[N:21][C:2]=1[C:34]1[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=1
Reactant: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2Cl)cc1OC
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2-c2cnn(C)c2)cc1OC
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)nicotinamide (1-3, 50.0 mg, 0.122 mmol)) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.3 mg, 0.122 mmol) in dioxanes (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (7.03 mg, 6.08 μmol) and 2 N aqueous sodium bicarbonate solution (0.304 mL, 0.608 mmol). Under microwave heating the deoxygenated mixture was held at 160° C. for 1 h. The reaction mixture was filtered and concentrated to dryness. A solid residue was triturated with ethyl acetate (4 mL), collected by filtration, washed with water (10 mL) and air dried to afford N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide (1-4). 1H NMR (300 MHz, DMSO) δ 9.09 (t, 1H, J=5.8 Hz), 8.87 (d, 1H, J=1.8 Hz), 7.92 (d, 1H, J=1.8 Hz), 7.82 (d, 1H, J=9.8 Hz), 7.39 (s, 2H), 7.06 (s, 1H), 6.92 (m, 3H), 4.29 (d, 2H, J=5.3 Hz), 3.74 (m, 6H), 3.32 (s, 3H), 2.35 (s, 3H). HRMS m/z (M+H) 457.2242 found, 457.2234 required.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:8][CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(C)=O
Reactant: [H][H]
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CCCCCC(C)Nc1ccccc1
Temperature: 150 °C
Yield: 37 %

Procedure:
A mixture of aniline (100 parts), 2-heptanone (220 parts), 4-toluene sulphonic acid (6 parts) and 3% palladium on carbon (5 parts) in a 1 litre autoclave was charged with hydrogen to a pressure of 80 atmospheres and heated at 150° C. for 40 hours. The cooled reaction mixture was diluted with ethyl acetate, filtered, washed with 1N-hydrochloric acid (6×200 parts) and water (2×200 parts), the ethyl acetate was separated and dried (MgSO4) before evaporating to leave N-(1methylhexyl)aniline (76 parts, 37%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]([F:23])([F:22])[C:16]([F:21])([F:20])[CH2:17][CH2:18]I.Cl>CN(C)C=O>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:18][CH2:17][C:16]([F:21])([F:20])[C:15]([Br:14])([F:23])[F:22])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: FC(F)(Br)C(F)(F)CCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCC(F)(F)C(F)(F)Br)C(=O)OCC
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In nitrogen atmosphere, 1900 mL of dimethylformamide was prepared with the addition of 320 g (7.17 mol) of sodium hydride (60% mineral oil-containing product), followed by putting it in an iced bath with the addition of 1208 g (7.17 mol) of diethyl malonate. After 1 hour of stirring, 2400 g (7.17 mol) of 1-bromo-1,1,2,2-tetrafluoro-4-iodobutane was added to this solution while regulating the reaction solution so as to be not higher than 100° C. After 1 hour of stirring, 1000 mL of 1N hydrochloric acid was added thereto, followed by extracting it with diisopropyl ether. Then, an organic layer was concentrated, followed by distillation under reduced pressure (115-116° C./0.53 kPa), thereby obtaining 1940 g of the objective 2-(4-bromo-3,3,4,4-tetrafluorobutyl)-malonic acid diethyl ester (74% yield, 89% GC purity) in the form of a light yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1I)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[B].C(OC1C=C(CC2C(N)=NC(N)=NC=2)C=C(OCC)C=1C1C=CC=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([O:20][CH2:21][CH3:22])[C:18]=1[C:25]1[CH:24]=[CH:23][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)[CH3:2]
Reactant: [B]c1ccc2ccccc2c1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Agent: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccccc1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc2ccccc2c1

Procedure:
Starting from 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (414 mg; 1 mmol) and naphthalen-2-yl-boron acid (690 mg; 4 mmol), 327 mg (79%) 5-(2,6-diethoxy-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine [sic] are obtained as a colourless powder.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[C:22][C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C#CCCCCCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc(C#CCCCCCc2ccccc2)n1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of 6-bromopyridine-2-caboxaldehyde (30.0 g), 7-phenyl-1-heptyne (26.8 g), triethylamine (48.9 g), bis(triphenylphosphine)palladium(II)chloride (2.3 g, 2%), and copper(I)iodide (0.31 g, 1%) in dry tetrahydrofuran (100 ml) was heated under nitrogen at 55° C. for 70 hrs. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate was washed with ethyl acetate. The filtrate was evaporated. The residue was dissolved in ethyl acetate, the solution washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The residue was flash chromatographed on silica gel, eluting with 0.5% to 2%-ethyl acetate:hexane. The appropriate fractions were collected and concentrated to yield 29.5 g of the product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:7]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6]1.Cl[C:27]1[N:32]=[C:31]([NH2:33])[C:30]([N+:34]([O-:36])=[O:35])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:33][C:31]1[N:32]=[C:27]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=3)[C:7]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:6]2)[CH:28]=[CH:29][C:30]=1[N+:34]([O-:36])=[O:35]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCc1ccc(-c2cn(CCCN)cc2NC(=O)OC(C)(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCc1ccc(-c2cn(CCCNc3ccc([N+](=O)[O-])c(N)n3)cc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
N-[1-(3-aminopropyl)-4-(4-ethylphenyl)pyrrol-3-yl] (tert-butoxy)carboxamide (1 eq) and 6-chloro-3-nitro-2-pyridylamine (1.2 eq) were dissolved in DMA with stirring under argon at rt. Hünig's Base (1.5 eq) was added to the clear dark brown solution which was heated to 60° C. for 12 hours until completion was determined by LC/MS and TLC, eluting with EtOAc/Hexane (3:2, v/v) (Rf=0.3). EtOAc was added to the reaction mixture which was then washed with water, brine, dried (Na2SO4), filtered, and concentrated to dryness to give the crude brown product. The brown residue was purified by silica column chromatography eluting with EtOAc/Hexane (24:26, v/v). After collecting the purified fractions and concentrating, the product was isolated as a light yellow solid (75% yield).
Reaction SMILES: [Ca].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][CH:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH3:11])[CH:7]=[CH:8][CH:9]=1.[ClH:25]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:25].[ClH:25].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc([C@@H](C)NC2CCN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Agent: [Ca]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)N[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 25 g of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate and 25.9 g of diisopropylethylamine dissolved in 500 ml of methylene chloride was added dropwise 100 ml of a solution of 49 g of anhydrous trifluoromethanesulfonic acid in methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., and then, to the mixture was added dropwise 100 ml of a solution of 24.2 g of (R)-1-(3-methoxyphenyl)ethylamine in methylene chloride at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate. (2) To a solution of 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate dissolved in 30 ml of chloroform was added 300 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 16 hours. The resulting precipitates were collected by filtration, washed with ethyl acetate, and recrystallized from methanol and tetrahydrofuran twice to obtain 8.54 g of (R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.003).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(=O)([O-])[O-]>CN(C=O)C.C(OCC)(=O)C>[P:20]([O:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1.5 g) and diethyl chlorophosphate (2 ml) in DMF (20 ml) there was added a powdered mixture of potassium carbonate (2 g) and potassium iodide (2 g). The reaction mixture was stirred at room temperature. After 30 minutes, a further addition of potassium carbonate and potassium iodide (2 g each) was made and stirring was continued. Two hours later more carbonate (2 g) and diethyl chlorophosphate (2 ml) were added, and then three hours later a final addition of carbonate (2 g) was made. The mixture was stirred for 3 days then diluted with ethyl acetate (60 ml) and the insolubles filtered. The filtrate was washed with water, dried and evaporated down. This residue was crystallized from acetone, then chromatographed on a column of silica gel, eluting first with 1:1, then 3:1 mixtures of ethyl acetate and hexane to afford pure title compound (337 mg), m.p. 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24](O)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[CH3:30][NH:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([N:31]([CH3:32])[CH3:30])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)N(C)C)s3)C[C@H]2OC)nc1Cl
Yield: 65.9 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (40 mg, 0.09 mmol), dimethylamine hydrochloride (9 mg, 0.11 mmol), WSC hydrochloride (59 mg, 0.31 mmol), HOBT (21 mg, 0.15 mmol), diisopropylethylamine (0.020 mL, 0.11 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 27 mg of the title compound as a yellow oily substance (62%).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:5][CH:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:3]1.FC(F)(F)C(O)=O.ClC1[N:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]2[S:36][C:37]([C:40]#[N:41])=[CH:38][N:39]=2)[CH:29]=1.C(N(CC)CC)C>C(O)CCC>[O:19]=[S:2]1(=[O:1])[CH2:3][CH:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[N:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]4[S:36][C:37]([C:40]#[N:41])=[CH:38][N:39]=4)[CH:29]=3)[CH2:10][CH2:11]2)[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CS(=O)(=O)C2)CC1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(Nc2cc(N3CCN(C4CS(=O)(=O)C4)CC3)ncn2)s1
Temperature: 150 °C

Procedure:
50-2 (0.20 g, 0.68 mmol) was first treated with trifluoroacetic acid (4 mL) for 30 minutes and then concentrated under reduced pressure. The residue was then dissolved in n-butanol (4 mL) to which 35-1 (0.16 g, 0.68 mmol) and triethylamine (0.34 g, 3.41 mmol) were added and then heated at 150° C. for 18 hours. Upon cooling the solid was filtered off, washed with n-butanol, ethyl ether and then purified on a silica column to yield 50-3. Hi-Res MS: calc: 392.0958 found: 392.0949. 1H-NMR (DMSO-d6): 12.10(s, 1H); 8.43(s, 1H); 8.26(s, 1H); 6.24(s, 1H); 4.28(m, 2H); 4.15(m, 2H); 3.57(br s, 4H); 3.22(m, 1H); 2.46(t, 4H).
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[Cl:15][C:16]1[C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][C:19]([NH:29][NH2:30])=[C:18]([F:31])[CH:17]=1>O.C(OCC)C>[Cl:15][C:16]1[C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][C:19]([N:29]([C:2]2[CH:1]=[CH:18][CH:17]=[CH:16][CH:21]=2)[N:30]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:18]([F:31])[CH:17]=1
Reactant: CC(=O)[O-]
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CCOC(=O)COc1cc(NN)c(F)cc1Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)COc1cc(N(N=CC(=O)C(F)(F)F)c2ccccc2)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 135.3 %

Procedure:
To a solution of 1.249 g of sodium acetate dissolved in 10 ml of water was added 1.366 g of 1,1-dibromo-3,3,3-trifluoroacetone, and the mixture was stirred at 80° C. for 30 minutes. The reaction solution was left cooling to room temperature, to which a solution of 1.00 g of 4-chloro-2-fluoro-5-(ethoxycarbonyl)methoxyphenylhydrazine dissolved in 10 ml of diethyl ether was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with 100 ml of ethyl acetate. The organic layer was washed with 100 ml of saturated aqueous sodium bicarbonate solution and then with 100 ml of saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to give a crude product. The crude product was recrystallized from toluene to give 1.151 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-(ethoxycarbonyl)methoxyphenylphenylhydrazone), compound 3-8.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:17]=[C:18]([Si:21]([CH3:24])([CH3:23])[CH3:22])[O:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1.CCCCCC>C(OCC)C.CCCCCC>[C:25]([O:1][CH:2]([C:16]1[CH:17]=[C:18]([Si:21]([CH3:22])([CH3:23])[CH3:24])[O:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=[O:27])[CH3:26]
Reactant: C[Si](C)(C)c1cc(C(O)CCCCCCCCc2cccs2)co1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=O)OC(CCCCCCCCc1cccs1)c1coc([Si](C)(C)C)c1

Procedure:
A solution of 4-(1-hydroxy-9-thiophen-2-ylnonyl)-2-trimethylsilylfuran (0.034 g, 0.093 mmol), acetic anhydride (1 ml) and pyridine (0.25 ml) was stirred at room temperature until no starting material was visible by TLC. The reaction mixture was concentrated and the residue taken up in ethyl ether, washed with 10% hydrochloric acid, saturated sodium chloride, aqueous 5% cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a pale oil. Purificatioon by flash chromatography (silica, 100% hexane to 5% ethyl ether/hexane) gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.S(=O)(=O)(O)O.[CH:16]1C=CC=CC=1>CO>[O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1ccc[nH]c1=O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc[nH]c1=O

Procedure:
A mixture containing 27.8 g of 1,2-dihydro-2-oxo-3-pyridinecarboxylic acid, 3.0 ml of concentrated sulfuric acid in 500 ml of methanol, and 300 ml of benzene are heated under reflux for 2.5 hours. A Dean-Stark trap is then attached, and the azeotrope collected is removed periodically in 25 ml fractions over a period of 28 hours. The remaining solvent is removed by evaporation under reduced pressure and the solid residue suspended in 500 ml of cold water. The suspension is filtered (from which unreacted starting material can be recovered) and the filtrate continuously extracted with methylene chloride. The extracts are concentrated under reduced pressure to yield the title compound as a white solid which, upon recrystallization from 1.4 L of benzene, yields 19.48 g (64%) of methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate: m.p. 148°-151° C.; NMR (DMSO-d6, 80 MHz) delta 3.72 (s, 3H), 6.25 (dd, 1H, J=7.1 Hz, J=6.3 Hz), 7.64 (dd, 1H, J=6.3 Hz, J=2.2 Hz), 8.03 (dd, 1H, J=7.1 Hz, J=2.2 Hz).
Reaction SMILES: [CH2:1]([CH:7]([CH2:9][NH2:10])O)[CH2:2][CH2:3][CH2:4]CC.C(N)CCCCC.[CH2:18]1[O:20][CH2:19]1>>[CH2:9]([NH:10][CH2:18][CH2:19][OH:20])[CH2:7][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCC(O)CN
Reactant: C1CO1
Solvent: CCCCCCN
Product: CCCCCCNCCO

Procedure:
In an alternate synthesis scheme for n-hexyl ethanolamine, the ethoxylation steps remained the same as above in sequence, temperature and pressure. However, the preferred weight fraction of n-hexyl amine to ethylene oxide was lowered to approximately 88 pounds n-hexyl amine to 12 pounds ethylene oxide to yield 100 pounds of reaction mass. The weight ratio of mono to di ethoxylates in the reaction mass was approximately 4.0-4.2 mono to 1.0 di. The purification section was also the same except the process was stopped after removal of n-hexyl amine overhead. The final bottoms fraction contained n-hexyl ethanolamine and some diethoxylates byproducts (less than 20% by weight).