Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][C@H:6]([C:20]([F:23])([F:22])[F:21])[C:7]([NH:9][C@H:10]([C:15]1[NH:19][N:18]=[N:17][N:16]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=O)C.[NH4+].[OH-].C(OCC)(=O)C.CO>O>[F:22][C:20]([F:21])([F:23])[C@@H:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:15]1[NH:19][N:18]=[N:17][N:16]=1)[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8]
Reactant: CC(=O)SC[C@@H](C(=O)N[C@@H](CC(C)C)c1nnn[nH]1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](CS)C(F)(F)F)c1nnn[nH]1
Reaction time: 0.03 h

Procedure:
To a suspension of (S,S)-2-[(acetylthio) methyl]-3,3,3-trifluoro-N-[3-methyl-1-(1H -tetrazol-5-yl)butyl]propanamide [prepared in Example 39(e), 1.034 g., 2.95 mmol.] in 6 mL of degassed water at room temperature under argon was added a mixture of concentrated NH4OH (1.95 mL) and water (1.95 mL). After two minutes, the reaction was quenched with saturated potassium bisulfate (pH 1.5) and extracted with ethyl acetate. The organic extracts were dried and purified by flash chromatography (50 mm×6 inch, 1:1 hexanes:ethyl acetate +0.5% acetic acid) to give 0.76 g. of white solid product. This material was combined with 25 mg. from a previous experiment and recrystallized from ethyl acetate/hexanes to give 0.69 g. of the title (S,S) isomer product as a white solid, m.p. 183°-184° C., TLC Rf =0.14 (1:1, hexanes:ethyl acetate +0.5% acetic acid). [α]D =-39.8° (c=0.57, methanol).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[CH2:25][C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:24][CH2:25][C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: C#CCCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 37.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.35 g) and 4-(but-3-yn-1-ylamino)-1,3-thiazol-2(5H)-one (1 g) in 2-propanol (20 mL) was added piperidinium acetate (0.58 g). The reaction mixture was stirred at 80° C. for 6 hr and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (0.73 g).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[S:7](=[O:11])(=[O:10])([OH:9])[OH:8]>>[OH:5][C:2]([CH3:6])([CH3:1])[C:3]([NH2:4])=[O:8].[S:7]([OH:11])([OH:10])(=[O:9])=[O:8].[OH:5][C:2]([CH3:6])([CH3:1])[C:3]([NH2:4])=[O:8]
Reactant: CC(C)(O)C#N
Agent: O=S(=O)(O)O
Product: CC(C)(O)C(N)=O

Procedure:
This preparation generally comprises the reaction of acetone cyanohydrin with concentrated sulphuric acid to give α-hydroxyisobutyramide and α-hydroxyisobutyramide sulphate. These two compounds are then heated to give sulphuric methacrylamide.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[N:20][C:13]=3[N:14]([CH2:18][CH3:19])[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:9][CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[CH:23]=[CH:22][C:21]([CH:24]([OH:25])[CH3:1])=[N:20][C:13]=3[N:14]([CH2:18][CH3:19])[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)O)nc21
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
1 M Methylmagnesium bromide (14 ml, 14 mmol) was added to a solution of 4.4 g (14 mmol) of 4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one-7-carbaldehyde in 50 ml of tetrahydrofuran under ice-cooling, followed by stirring for 30 minutes under ice-cooling. Then, 7 ml (7 mmol) of 1 M methylmagnesium bromide was added and the mixture was stirred for 30 minutes under ice-cooling. Then, saturated ammonium chloride aqueous solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) to give 1.4 g of 4-(3-chlorophenyl)-1-ethyl-7-(1-hydroxyethyl)pyrido[2,3-d]pyrimidin-2(1H)-one. The yield was 30%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[I:9].[C:10]([C:13]1[S:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[C:10]([C:13]1[S:17][C:16]([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=2)=[O:19])=[CH:15][CH:14]=1)(=[O:12])[CH3:11]
Reactant: Nc1ccc(Cl)c(I)c1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(I)c2)s1

Procedure:
4-Chloro-3-iodoaniline (2.5 g, 9.88 mmol) was used in Procedure E with 5-acetylthiophene-2-carboxylic acid (1.85 g, 10.8 mmol) at 23° C. for 2 hours. The crude material was purified by silica gel chromatography (20-100% ethyl acetate/hexanes) to yield 5-Acetyl-N-(4-chloro-3-iodophenyl)thiophene-2-carboxamide as a yellow solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Cl[Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23]>O>[I:1][C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH:3]=1
Reactant: COc1ncnc2[nH]cc(I)c12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncnc2c1c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.33 h
Yield: 34.2 %

Procedure:
5-Iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (35, 3.4 g, 12.0 mmol) and 20 mL of N,N-dimethylformamide were combined in a round bottom flask and sodium hydride (350 mg, 8.8 mmol) was added at room temperature. After 20 minutes, chloro-triisopropyl-silane (36, 1.9 mL, 8.8 mmol) was added. The reaction was stirred for 2 hours, then poured into water and extracted 3× with ethyl acetate. The organic layers were combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel flash column chromatography eluting with 0-25% ethyl acetate in hexane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (37, 1.3 g).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[O:25]=[S:26]1(=[O:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:29]3[CH2:30][CH2:31][S:26](=[O:32])(=[O:25])[CH2:27][CH2:28]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C(Nc1ncc(CN2CCS(=O)(=O)CC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 17.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol), 1,1-dioxo-thiomorpholine hydrochloride (52 mg, 0.30 mmol) and sodium triacetoxyborohydride (51 mg, 0.24 mmol) to afford 16 mg (18%) of the desired product after purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[C:3]=1[NH:10][C:11]([C:13]1[S:17][C:16]([NH:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][CH:14]=1)=[O:12].CN1CCOCC1.[CH3:45][C:46]([CH3:51])([CH3:50])[C:47](Cl)=[O:48].[NH4+].[Cl-]>C1COCC1.O>[C:47]([O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:10][C:11]([C:13]1[S:17][C:16]([NH:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][CH:14]=1)=[O:12])(=[O:48])[C:46]([CH3:51])([CH3:50])[CH3:45]
Reactant: O=C(Nc1c(Cl)cccc1CO)c1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)OCc1cccc(Cl)c1NC(=O)c1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
To a solution of compound 7a (7.36 g, 14 mmol) in THF (200 mL) at 5° C. were added N-methylmorpholine (3.1 mL, 28 mmol) followed by slow addition of trimethylacetyl chloride (8a, 1.8 mL, 21 mmol). The reaction mixture was allowed to warm to room temperature over a period of 3 h. A solution of saturated NH4Cl in H2O (500 mL) was added. The mixture was extracted with EtOAc (2×250 mL). The combined extracts were washed with 1N HCl (500 mL), saturated NaHCO3 (500 mL), dried over MgSO4. The solution was filtered and concentrated in vacuo to give compound 9a as a white solid (8.90 g, 100% yield). 1H NMR (500 MHz, CDCl3) δ 1.16 (s, 9H), 5.01 (s, 2H), 7.20-7.40 (m, 18H), 7.79 (s, 1H), 8.30 (bs, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si](OCC)(OCC)OCC.C=[O:16].O.[C:18]1(C)C=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:16]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=2[CH:3]=[CH:2][NH:1]1
Reactant: C=O
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: Cc1ccccc1
Solvent: O
Product: C1=Cc2ccccc2ON1
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask was charged with 3-aminopropyltriethoxysilane (44.2 g, 200 mmol), paraformaldehyde (15.0 g, 500 mmole), siloxane bridged bisphenol (26.8 g, 100 mmole, prepared as described in Example 10A), and toluene (200 ml). A magnetic stir bar was added to the flask, which was fitted with a Dean-Stark trap and condenser. The reaction mixture was heated to reflux for 4.0 hours while stirring. A total of 7.2 ml (400 mmole) of water was collected. The reaction mixture was allowed to cool to room temperature and then passed through a thin layer of silica gel. The toluene solvent was removed by rotary evaporation and the residue remaining in the flask was sparged with nitrogen gas for four hours while the flask was maintained at 60° C. The final product was a slightly red, moderately viscous liquid. The yield of this bisbenzoxazine was 80% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]([CH3:31])([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[NH2:25]>>[CH3:23][C:24]([NH:25][C:14]([C:12]1[CH:11]=[CH:10][C:9]([N:17]2[CH2:20][C:19]([F:21])([F:22])[CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:15])([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[CH3:31]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 140 a) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=449.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.F[B-](F)(F)F.[CH3:13][C:14]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[Se+:18]=1)([CH3:16])[CH3:15].[Cl:28][C:29]1[C:30](=[O:36])[C:31]([Cl:35])([Cl:34])[C:32]=1Cl.[OH-].[Na+]>ClCCl>[CH3:16][C:14]([C:17]1[Se:18][C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:21](=[CH:23][C:32]2[C:31]([Cl:35])([Cl:34])[C:30](=[O:36])[C:29]=2[Cl:28])[CH:22]=1)([CH3:13])[CH3:15]
Reactant: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Reactant: O=C1C(Cl)=C(Cl)C1(Cl)Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)[Se]1
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution of triethylamine (14.8 g, 147 mmol) in dichloromethane (40 mL) was added dropwise under nitrogen to a solution of 2,6-bis(1,1-dimethylethyl)-4-methylselenopyrylium tetrafluoroborate (26.2 g, 73.4 mmol, prepared in Examples 4 and 5 above) and 2,3,4,4-tetrachlorocyclobut-2-en-1-one (15.2 g, 73.4 mmol) in dichloromethane (60 mL), contained in a flask equipped with a condenser and an outlet connected to a gas-washing bottle containing 10% aqueous sodium hydroxide solution; the addition was effected at a rate such that the temperature of the reaction mixture did not exceed 35° C. After the addition had been completed, the reaction mixture was stirred for one hour, then applied to a column packed with silica gel. Elution with dichloromethane, followed by evaporation of the solvent under reduced pressure, provided the crude product which was further purified by trituration with trifluoroethanol for one hour to give 3-[[2,6-bis(1,1,-dimethylethyl)-4H-selenopyran-4-ylidene]methyl]-2,4,4-trichlorocyclobut-2-en-1-one (23 g, 71% yield) as maroon crystals. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH:7]([CH3:18])[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[N+:19]([O-])([OH:21])=[O:20]>[S]>[Cl:6][CH:7]([CH3:18])[CH:8]([N+:19]([O-:21])=[O:20])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CC(Cl)CCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [S]
Product: CC(Cl)C(CC(=O)c1ccccc1)[N+](=O)[O-]

Procedure:
50 ml of concentrated sulphuric acid are treated, while stirring, with 9.9 g of 4-chloro-valerophenone, while cooling with an ice/sodium chloride mixture. The bulk of the product dissolves, a slightly exothermic reaction taking place, and a yellow suspension forms, which is treated, while stirring vigorously and at a temperature of -10° to -5°, with a mixture of 20 ml of concentrated sulphur acid and 10.4 ml of concentrated nitric acid (d = 1.52), in the course of 10 minutes. After a reaction time of five minutes, the mixture is poured onto ice and the aqueous mixture is extracted with chloroform. The organic extract is washed once with an aqueous solution of sodium carbonate and with water, dried over sodium sulphate and filtered through silica gel. 4-Chloro-3-nitro-valerophenone is obtained as an oily residue after evaporating the filtrate.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:6](O)=[O:7])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>CN(C)C=O>[CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:6]([Cl:19])=[O:7])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1C(=O)O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,6-diisopropylbenzoic acid (12.8 g, 0.062 mol), oxalyl chloride (25 mL), and dimethylformamide (2 drops) was stirred overnight at room temperature. The volatiles were removed on the rotary evaporator and the residue dried to yield an orange oil, 12.65 g, 90.9%.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21](=[O:26])[C:20]([C:27](N(OC)C)=[O:28])=[N:19]2)=[C:14]([F:33])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[C:27]([C:20]1[C:21](=[O:26])[C:22]([O:24][CH3:25])=[CH:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:13][C:14]=2[F:33])[N:19]=1)(=[O:28])[CH3:1]
Reactant: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(C(=O)N(C)OC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 84.6 %

Procedure:
MeMgBr (1 M solution in THF, 56.4 mL, 56.4 mmol) was added dropwise at −78° C. to a solution of 1-[4-(benzyloxy)-2-fluorophenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (7.77 g, 18.8 mmol) in THF (120 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (5.86 g, 85% yield) as a pale yellow solid: mp 101-103° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.67 (3H, s), 3.89 (3H, s), 5.13 (2H, s), 6.84-6.93 (2H, m), 7.34-7.44 (5H, m), 7.48-7.55 (1H, m), 7.69 (1H, d, J=2.3 Hz). Anal. Calcd for C20H17FN2O4: C, 65.21; H, 4.65; N, 7.60. Found: C, 65.37; H, 4.68; N, 7.47.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([O:24]CCCC)=[O:23])=[C:18]([O:29][CH3:30])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.FC1C=CC2N=C(NC3C=CC(C4C=CC(C(OC)=O)=C(OC)C=4)=CC=3)SC=2C=1.CO.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]([O:29][CH3:30])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCCCOC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1OC
Agent: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)ccc1C(=O)O
Temperature: 50 °C

Procedure:
Butyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-carboxylate (0.30 g, 0.43 mmol) and methyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-carboxylate (0.13 g, 0.25 mmol) were combined in THF (6 mL), MeOH (6 mL) and water (3 mL), and then NaOH (0.09 g, 2.1 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure, acidified, and the resulting solid was collected by filtration. This yielded 0.286 g (87%) of the title compound. LC/MS m/z 395.2 (MH+), retention time 3.30 min. 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 3H), 7.12-7.33 (m, 3H), 7.61-7.90 (m, 7H), 10.62 (br, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH2:19]>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1/[CH:18]=[CH:19]/[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: C=Cc1ccccn1
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\c1ccccn1

Procedure:
The product of Example 1B (110 mg, 0.38 mmol; Aldrich) and 2-vinylpyridine (40 mg, 0.38 mmol; Aldrich) were processed as described in Example 1D to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.04-2.17 (m, 4 H), 3.04-3.12 (m, 2 H), 3.13-3.17 (m, 1 H), 3.26 (ddd, J=14.1, 8.5, 5.8 Hz, 2 H), 4.25 (s, 2 H), 7.04 (t, J=7.6 Hz, 1 H), 7.26 (ddd, J=7.4, 5.0, 1.1 Hz, 1 H), 7.28-7.34 (m, 2 H), 7.41 (d, J=7.3 Hz, 1 H), 7.71-7.74 (m, J=7.9 Hz, 1 H), 7.82 (td, J=7.6, 1.8 Hz, 1 H), 7.93-8.01 (m, 1 H), 8.51 (dd, J=5.0, 0.8 Hz, 1 H); MS (APCI) m/z 316 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.CO>[OH-].[K+].CCO.C(Cl)Cl>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[C:21](=[CH:32][C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19]3)[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Reactant: O=Cc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: O=C1C(=Cc2cccs2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 43.9 %

Procedure:
According to the method of Example 32, Step 2, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.356 g, 1.0 mmol) was reacted with thiophene-2-carboxaldehyde (0.174 g, 1.55 mmol) in 5 mL of 4% KOH in EtOH for 24 hours to afford, after chromatography (silica gel, 60 g; 8% MeOH in DCM), 0.154 g (40%) of the title compound as a red glassy solid, mp 60-63° C.: CI-MS m/e 351 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1.O[N:29]1[C:33]2C=[CH:35][CH:36]=[CH:37][C:32]=2N=N1.N1CCCCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([N:29]3[CH2:35][CH2:36][CH2:37][CH2:32][CH2:33]3)=[O:22])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1nnc2n1-c1sc(CCC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1nnc2n1-c1sc(CCC(=O)N3CCCCC3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a solution of 1.1 g of 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.25 g of piperidine and stirred at room temperature for 10 minutes. To the mixture is added 0.65 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 1 hour and furthermore stirred at room temperature for 20 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 50 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from ethyl acetate. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 0.9 g of 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4 ]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid piperidide as colorless crystals, melting at 157°-160° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[O:24][C:23]([CH3:26])=[CH:22][C:21]3=[O:27])[C:6]2[C:11](=[O:12])[NH:10][CH:9]=[N:8][C:7]=2[NH:13][C:14]=1[CH3:15])(=[O:3])[CH3:2].F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].CO>ClCCl>[C:1]([C:4]1[CH:5]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[O:24][C:23]([CH3:26])=[CH:22][C:21]3=[O:27])[C:6]2[C:11]([O:12][CH2:33][CH3:34])=[N:10][CH:9]=[N:8][C:7]=2[NH:13][C:14]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC[O+](CC)CC
Reactant: CC(=O)C1=C(C)Nc2nc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOc1ncnc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
140 mg (0.38 mmol) of 6-acetyl-7-methyl-5-(2-methyl-4-oxo-4H-chromen-8-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one are suspended under an argon atmosphere in dichloromethane (7 ml), 219 mg (1.15 mmol) of triethyloxonium tetrafluoroborate are added, and the mixture is stirred at RT for 12 h. The reaction mixture is then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 9 mg (6% of theory) of the title compound are obtained as a white solid.