Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:26][CH:25]=1
Reactant: COc1ccc(CCCBr)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 90 °C

Procedure:
(R)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo [b,e][1,4]oxazepine (Preparation Example 1) (280 mg, 1.0 mmol), 3-(4-methoxyphenyl)-1-propyl bromide (320 mg, 1.4 mmol), sodium carbonate (150 mg, 1.4 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (20 ml), and the mixture was heated under reflux at 90° C. for 13 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned in ethyl acetate and water. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was treated by the column chromatography and then eluted with dichloromethane as the eluent. A suitable fraction was collected, and the solvent was evaporated under reduced pressure to obtain the title compound in the form of a light yellow oil (310 mg, 72%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.[NH2:11][CH2:12][C:13]([N:15]1[CH:19]([CH3:20])[C:18](=[O:21])[NH:17][C:16]1([CH3:23])[CH3:22])=[O:14]>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:11][CH2:12][C:13]([N:15]1[CH:19]([CH3:20])[C:18](=[O:21])[NH:17][C:16]1([CH3:22])[CH3:23])=[O:14])=[O:10]
Reactant: CC1C(=O)NC(C)(C)N1C(=O)CN
Reactant: O=C(O)CN1CCCC1=O
Product: CC1C(=O)NC(C)(C)N1C(=O)CNC(=O)CN1CCCC1=O

Procedure:
The same procedure of example 11, starting form 2-oxo-1-pyrrolidineacetic acid and 1-(2-aminoacetyl)-2,2,5-trimethyl-4-imidazolidinone, gave the title compound, m.p. 213°-215° C. dec.
Reaction SMILES: CN([CH2:4][C:5]1[C:6]2[S:16][CH:15]=[CH:14][C:7]=2[NH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])C.CI.[BH4-].[Na+].Cl.CC1CCCCC1.C>>[CH3:4][C:5]1[C:6]2[S:16][CH:15]=[CH:14][C:7]=2[NH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1[nH]c2ccsc2c1CN(C)C
Agent: C
Agent: Cl
Agent: [BH4-]
Solvent: CI
Solvent: CC1CCCCC1
Product: COC(=O)c1[nH]c2ccsc2c1C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Under N2, to methyl 6-[(dimethylamino)methyl]-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.34 g, 1.45 mmol) was added methyl iodide (1.48 mL, 2.37 mmol). The mixture was allowed to stand at rt for 1 h, and then the methyl iodide was removed. The resulting salt was dissolved in absolute methanol (5 mL). To this solution was carefully added sodium borohydride (1.23 g, 3.25 mmol) in small portions. After the addition was complete, the reaction mixture was diluted to a volume of 25 mL by the addition of 3N hydrochloric acid. The mixture was stored in the refrigerator overnight, and then the blue precipitate was dissolved in boiling methylcyclohexane, and the solution was treated with Darco (activated carbon) and filtered. The filtrate was evaporated and purified by chromatography over silica gel (0 to 40% EtOAc in heptane over 30 min) to give methyl 6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.12 g, 43%). 1H NMR (400 MHz, CDCl3) δ ppm 2.53 (s, 3H) 3.91 (s, 3H) 6.92 (d, J=5.27 Hz, 1H) 7.32 (d, J=5.32 Hz, 1H) 8.81 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:4][C:3]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(C)c(N)c(Br)c1
Product: Cc1cc(C)c(N)c(-c2ccccc2)c1

Procedure:
2-Bromo-4,6-dimethylaniline was coupled with phenyl boronic acid under Suzuki conditions to give 2-amino-3,5-dimethylbiphenyl in 68% yleld.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:7]([C:18](=[O:20])[NH2:19])[C:8]1[C:9]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)([CH3:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1.C(OCC)(=O)C>CC(N(C)C)=O.[Cu](I)I.O>[CH2:1]([O:3][P:4]([CH:7]([C:8]1[C:9]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)[C:18](=[O:20])[NH:19][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)([CH3:6])=[O:5])[CH3:2]
Reactant: Fc1ccc(C=CBr)cc1F
Reactant: CCOP(C)(=O)C(C(N)=O)c1csc2ccc(Cl)cc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(C)(=O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
[Carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid ethyl ester (60.0 g, 181 mmol) was placed in a reactor under nitrogen, followed by addition of cesium carbonate (35.3 g, 108 mmol) and copper iodide (6.90 g, 36.2 mmol) and the resulting mixture was stirred at ambient temperature. DMA (123 g) and N,N′-dimethylethylenediame (6.36 g, 72.1 mmol) (with the addition flask washed with DMA (30 g)) were added and the resulting mixture heated to 70-75° C. with about 30-60 minutes, over which time a thin blue suspension was observed to form. To the resulting mixture was then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (47.6 g, 217 mmol) over about 10-30 minutes (with the addition flask washed with DMA (30 g)), then stirred for 5 to 7 hours at 75-85° C., with the progress of the reaction monitored by HPLC. When the reaction was deemed complete, the reaction mixture was cooled to 60-78° C., ethyl acetate (345 g) was added followed by addition of water (303 g), and the mixture stirred for 10-30 minutes. The resulting phases were separated. To the organic phase was added a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated, to the organic phase was added again a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated and treated a third time with addition of a solution of NaCl (30 g in 270 g H2O), followed by stirring for 10-30 min at a temperature of 55-65° C. The resulting phases were separated, the organic phase heated to distill off 107-139 g of solvent (at 50-65° C.). To the resulting residue, cyclohexane (280 g) was added over 20-40 minutes and the resulting mixture cooled to 10-15° C., then stirred at this temperature for 2-3 hours, over which time a thick suspension was observed to form. The resulting suspension was filtered, the filtercake washed with a mixture of cyclohexane (135 g) and ethyl acetate (45 g), then dried at 55-60° C., under vacuum to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[C:3]([NH:5][CH:6]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][N:8]([CH3:19])[C:7]1=[O:20])=[O:4].[OH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25].O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[OH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24]([NH:1][C@H:2]([C:3](=[O:4])[NH:5][C@H:6]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][N:8]([CH3:19])[C:7]1=[O:20])[CH3:21])=[O:25]
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: C[C@H](N)C(=O)NC1C=C(c2ccccc2)C=CN(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N[C@H]1C=C(c2ccccc2)C=CN(C)C1=O
Temperature: 1 °C
Reaction time: 4.5 h
Yield: 92.1 %

Procedure:
The (S)-2-amino-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-azepin-3-yl)-propionamide (406 g, 1.423 mol) is combined with dichloromethane (3 L) and the solution cooled to 0-2° C. To this solution is added (S)-2-hydroxy-3-methyl-butyric acid (168.1 g, 1.423 mol), hydroxybenzotriazole hydrate (239.7 g, 1.565 mol) and diisopropylethylamine (310 mL, 1.779 mol) which provides a slight exotherm. The contents are cooled back to about 4° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (286.5 g, 1.494 mol) is added. The reaction contents are allowed to gradually warm to room temperature. High-performance liquid chromatography analysis at 4.5 hours (temperature at 14° C.) indicates about 5% unreacted starting amine present. After stirring an additional 1-1.5 hour, the reaction contents are quenched into water (1000 mL) and the layers are separated. The dichloromethane layer is further extracted with water (1000 mL), 0.1 N HCl (1000 mL), saturated sodium bicarbonate (1000 mL) and finally saturated aqueous sodium chloride. The dichloromethane layer is then dried over magnesium sulfate, filtered and concentrated via rotary evaporation to provide the crude diastereomeric mixture (505 g) of the coupled product as tan foam. The isomers are separated by chiral chromatography employing a Chiralpak® AD column eluting with 100% methanol. Upon removal of the elution solvent from the isomer fractions, approximately 210 g of the first eluting isomer is recovered as a tan foam and for the desired isomer 2, approximately 220 g (44%) is recovered, also as a tan powder. The second eluting isomer is the desired (S,S,S)-diastereomer. Approximately 140 g of the title compound is taken up in acetone (1000 mL) and water (95 mL). The solution is heated on the rotary evaporator until no suspended particles are observed. The solution is transferred to a flask, equipped with overhead stirring, and water (2750 mL) is gradually added over 15 minutes. The resulting slurry is allowed to cool to room temperature, then filtered and the cake is rinsed with 20% acetone/water solution (650 mL). After vacuum drying at 40° C. overnight, approximately 102 g of the title example is recovered.
Reaction SMILES: [N:1]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ncnc2ncccc12
Yield: 16.7 %

Procedure:
A solution of pyrido[2,3-d]pyrimidin-4-ol (490 mg, 3.33 mMol), triethylamine (4.4 mL, 31.6 mMol), and phosphorous oxychloride (2.8 mL, 30 mMol) was heated at reflux for 2 hours. The mixture was concentrated in-vacuo, and the residue was stripped from methylene chloride (3×50 mL) to remove excess phosphorous oxychloride. The residue was dissolved in ethyl acetate (100 mL), saturated sodium bicarbonate (100 mL) was added carefully, causing vigorous gas evolution, and the mixture was stirred for ten minutes. The layers were separated, the organic phase was washed with saturated sodium bicarbonate (30 mL), water (30 mL), brine (30 mL), dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with 40% ethyl acetate/heptane, to yield 92 mg of a tan solid as product. MS (ES+)=166 (M+H)+. Yield=17%.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]1[C:26]([F:27])=[CH:25][C:24]([C:28]#[N:29])=[C:23]([Cl:30])[N:22]=1>CS(C)=O.O>[F:27][C:26]1[C:21]([N:4]2[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]2=[O:13])=[N:22][C:23]([Cl:30])=[C:24]([C:28]#[N:29])[CH:25]=1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2nc(Cl)c(C#N)cc2F)c1=O
Temperature: 130 °C

Procedure:
A mixture of 0.776 g 1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidin-dione, 0.760 g potassium carbonate and 0.768 g 2,6-dichloro-3-fluoro-5-cyanopyridin in 40 ml dimethylsulfoxide is stirred under nitrogen at 130° C. until conversion is complete. Then the reaction mixture is cooled down and diluted with ice and water. The pH of the mixture is adjusted to neutral and the mixture is extracted several times with ethyl acetate. The organic layers are washed with water, dried, evaporated and the residue is purified by silicagel chromatography (hexane/ethyl acetate 7/3) to yield the title compound as a solid of m.p. 146-148° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[CH3:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[F:21][C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:34]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12)=[O:35])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4])([F:22])[CH3:20]
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(F)(F)c1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(F)(F)c1cccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol (0.40 g, 1.42 mmol) in acetonitrile (10 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.28 g, 1.49 mmol) and 1-hydroxybenzotriazole monohydrate (0.22 g, 1.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.49 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, 2:1) and recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (0.50 g, 78%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[O:15])=[CH:12][C:7]=2[C:6]([CH3:28])([CH3:27])[CH2:5][CH2:4][C:3]1=[O:29].[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[O:15])=[CH:12][C:7]=2[C:6]([CH3:27])([CH3:28])[CH2:5][CH2:4][C:3]1=[O:29]
Reactant: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1C(=O)CCC(C)(C)c2cc(NC(=O)c3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
1.00 g of ethyl p-[(2,3,4,5-tetrahydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepin-7-yl)carbamoyl]benzoate in 75 ml of ethanol/water (2:1) was treated with 0.40 g of sodium hydroxide and the reaction mixture was stirred at room temperature overnight. Thereafter, it was poured on to ice/conc. hydrochloric acid, extracted with ethyl acetate, the extract was washed with saturated sodium chloride solution, dried and concentrated up to crystallization. There was obtained 0.79 g of p-[(2,3,4,5-tetra- hydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepin-7-yl)carbamoyl]benzoic acid, m.p. >275° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][NH:22][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1cc(Br)c(CCl)cc1F
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)NCc1cc(F)c(F)cc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of 1-bromo-2-chloromethyl-4,5-difluorobenzene are dissolved in 5 ml of acetonitrile. 540 mg of caesium carbonate and 123 μl of tert-butylamine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness, after which the product is isolated as oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:9][NH2:10])=[CH:5][CH:6]=1.C(O[CH:14]=[C:15]([C:21]([CH3:23])=O)[C:16]([O:18]CC)=[O:17])C>>[CH3:23][C:21]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:9]([CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[N:10]=1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Reactant: NNCCc1ccccc1
Product: Cc1nn(CCc2ccccc2)cc1C(=O)O
Yield: 37.1 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 1 using phenelzine (15 g) and ethyl 2-ethoxymethyleneacetoacetate (12 g), the residue was recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to give 3-methyl-1-phenethylpyrazole-4-carboxylic acid (5.5 g).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27]([NH:29][CH:30]=[C:31]([C:37]([O:39]CC)=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>CCCCCC>[C:14]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[N:24]=[CH:25][C:26]3[C:37](=[O:39])[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][NH:29][C:27]=3[N:28]=2)[CH2:21][CH2:22]1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C(=CNc1ccnc(N2CCN(C(C)=O)CC2)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To diphenyl ether (16ml) kept at 250°-255° C. was added with stirring diethyl N-[2-(4-acetyl-1-piperazinyl)-4-pyrimidinyl]-aminomethylenemalonate (2.0g). The mixture was gently refluxed for 10 minutes, and then allowed to cool to room temperature. To the mixture was added n-hexane (12ml). The resulting precipitate was collected, washed with ethanol, and recrystallized from ethanol to yield ethyl 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d] pyrimidine-6-carboxylate (1.52 g), m.p. 300°-302° C. (decomp.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1>>[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:7]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1CNCCN1
Product: CC1CN(c2ccc(C#N)cn2)CCN1
Yield: 45 %

Procedure:
This compound was synthesized from 2-methyl-piperazine and 6-chloronicotinonitrile as described for example 39 step 1 (90 mg, yield 45%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=2.0 Hz, 1H), 7.79 (dd, J=9.2 Hz, J=2.4 Hz, 1H), 6.89 (d, J=9.2 Hz, 1H), 4.24 (t, J=10.2 Hz, 2H), 2.94-2.87 (m, 1H), 2.86-2.77 (m, 1H), 2.63-2.55 (m, 2H), 2.45-2.41 (m, 1H), 0.99 (d, J=6.1 Hz, 3H)
Reaction SMILES: [ClH:1].CO[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:22])[N:21]=2)=[CH:7][CH:6]=1.CC=C(C)C.B(Br)(Br)[Br:30]>C(Cl)(Cl)Cl>[ClH:1].[Br:30][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:22])[N:21]=2)=[CH:7][CH:6]=1
Reactant: COCc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Reactant: BrB(Br)Br
Agent: CC=C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(c2ccccc2-c2ccc(CBr)cc2)=N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g of 4'-methoxymethyl-2-(4,4-dimethyl-2-oxazolinyl)biphenyl hydrochloride, prepared in B/, are dissolved in 75 ml of chloroform stabilised with amylene, and 3.2 ml of boron tribromide are added while cooling to 0° C. The mixture is stirred for one hour at 0° C. and washed with cold water. The organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated under vacuum to give 5.2 g of 4'-bromomethyl-2-(4,4-dimethyl-2-oxazolinyl)biphenyl hydrochloride in the form of crystals of melting point 126°-127° C.
Reaction SMILES: C([NH:4][C@H:5]([C:25]([OH:27])=[O:26])[CH2:6][C:7]1[CH:14]=[C:12]([I:13])[C:11]([O:15][C:16]2[CH:23]=[C:21]([I:22])[C:20]([OH:24])=[C:18]([I:19])[CH:17]=2)=[C:9]([I:10])[CH:8]=1)(=O)C>B([O-])([O-])[O-].CN(C=O)C>[NH2:4][C@H:5]([C:25]([OH:27])=[O:26])[CH2:6][C:7]1[CH:8]=[C:9]([I:10])[C:11]([O:15][C:16]2[CH:17]=[C:18]([I:19])[C:20]([OH:24])=[C:21]([I:22])[CH:23]=2)=[C:12]([I:13])[CH:14]=1
Reactant: CC(=O)N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: [O-]B([O-])[O-]
Solvent: CN(C)C=O
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
STI is dissolved in 50 ml of borate-saline buffer pH 8.5, to a concentration of 16 mg/ml (38 μmole). N-hydroxysuccinimide ester of N-acetyl thyroxine (378 μmole, 346 mg) is dissolved in 50 ml of DMF in a separate container. Aliquots (2 ml) of the active ester in DMF are added to the STI at 5 minute intervals until all the active ester has been added. The reaction mixture is stirred at room temperature for an additional 3.5 hours, then terminated by dialysis against 2 liters of aqueous triethylamine pH 11. Chromatography of the product on a Sephadex G-75 column (5×100 cm) equilibrated with aqueous triethylamine, pH 11 is then conducted to isolate thyroxine (T4) conjugated to soybean trypsin inhibitor from free T4. Fractions containing 1-2 molecules of thyroxine per molecule of protein are isolated as the preferred reagent. Higher substituted fractions were obtained, although operable, they were less preferable.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]([O:13]CC1C=CC=CC=1)=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(OP(CCC(OCC)=O)(OCC)=O)C.O.CCCCCC>C(O)C>[CH2:7]([O:6][P:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CCC(=O)OCc1ccccc1)OCC
Agent: CCOC(=O)CCP(=O)(OCC)OCC
Solvent: CCCCCC
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCC(=O)O)OCC
Reaction time: 4 h

Procedure:
40.3 mmol of benzyl 3-diethylphosphonopropionate (12.1 g) are dissolved in 100 ml of ethanol, and 2 g of catalyst (5% Pd/C) are added. After stirring under an H2 atmosphere for 4 h, the active carbon is filtered off, and the solvent is distilled out. The product results as a colourless oil which slowly solidifies to a colourless solid at room temperature. The product is slightly contaminated with ethyl 3-diethylphosphono-propionate which, where appropriate, can be transferred into the organic phase by shaking several times with water and hexane, and be removed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:44][C:45]([F:54])([F:53])[C:46]1[N:51]=[C:50]([NH2:52])[CH:49]=[CH:48][CH:47]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:52][C:50]4[CH:49]=[CH:48][CH:47]=[C:46]([C:45]([F:53])([F:44])[F:54])[N:51]=4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4cccc(C(F)(F)F)n4)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 81 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 6-(trifluoromethyl)pyridin-2-amine yielded the title compound (81% yield) as a pale yellow foam. MS (ISP): m/z=735.4 [M+H]+.