Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:7]=2[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:4].[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:6]2[C:5]([C:3]([C:36]3[CH:35]=[CH:34][C:33]([O:32][CH2:31][CH2:30][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:38][CH:37]=3)=[O:4])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[S:8][C:7]=2[CH:18]=1
Reactant: Br[Mg]c1ccc(OCCN2CCCCC2)cc1
Reactant: COC(=O)c1c(-c2ccc(OC)cc2)sc2cc(OC)ccc12
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
To a solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid methyl ester (202 mg, 0.615 mmol) in tetrahydrofuran (5 ml) under nitrogen at 5° C. is added, dropwise over 2 min via syringe a solution of 4-[2-(1-piperidinyl)ethoxy]phenylmagnesium bromide (1.0 ml of 0.76 M solution, 0.76 mmol). Cooling is removed, and the reaction is allowed to stir at room temperature for 48 hours. It is then quenched by addition of saturated aqueous ammonium chloride (2 ml), and partitioned between methylene chloride and water. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated to an oil, which is chromatographed on silica (5:1:1 hexanes:dichloromethane:triethylamine) to afford recovered starting material (46.0 mg, 23%) and title compound. The latter is further purified by dissolution in methylene chloride, followed by washing with 1 N hydrochloric acid, then 1 N sodium hydroxide. Drying over magnesium sulfate, filtration and concentration furnished 97.4 mg of title compound (0.194 mmol, 32%, 41% based on recovered starting material). IR (CHCl3): 2932, 1647, 1597, 1475, 1252, 1163, 1029, 828 cm-1 ; 1H NMR (CDCl3) δ7.75 (d, 2H, J=8.7), 7.51 (d, 1H, J=8.7), 7.31 (m, 3H), 6.94 (dd, 1H, J=9.0, 2.4), 6.74 (m, 4 H), 4.07 (t, 2H, J=6.0), 3.87 (s, 3H), 3.73 (s, 3H), 2.72 (t, 2H, J=6.0), 2.47 (m, 4 H), 1.58 (m, 4 H), 1.42 (m, 2H); 13C NMR (CDCl3) d 193.2, 163.1, 159.8, 157.7, 142.5, 140.1, 134.1, 132.4, 130.7, 130. 5, 130.3, 126.1, 124.1, 114.8, 114.3, 114.1, 104.6, 66.3, 57.8, 55.7, 55.3, 55.2, 26.0, 24.2. Anal. Calcd. for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79; S, 6.39. Found: C, 71.56; H, 6.27; N, 2.82; S, 6.26.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([NH:24][N:25]=[CH:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[C:4]2[CH3:9])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2C=NNc2ccccc2)C(C)=C1C
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (20.0 mmol) in ethanol (60.0 mL) was added dropwise phenylhydrazine (22.0 mmol) and the mixture was stirred at room temperature for 2-hrs. The solvent was distilled off under reduced pressure and the residue was recrystallized from hexane to give 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde phenylhydrazone (4.8 g, yield 76.3%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:23])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:21]([NH:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)([CH3:23])[CH3:20]
Reactant: CC(C)=O
Reactant: CN1CCN(C(=O)c2nc3c(N)cccc3[nH]2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Nc1cccc2[nH]c(C(=O)N3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (4-amino-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 43; 50 mg, 0.19 mmol) in dichloroethane (10 mL), was added acetone (0.07 mL, 0.96 mmol) and acetic acid (10 drops), followed by NaBH(OAc)3 (203 mg, 0.96 mmol). The reaction mixture was stirred at room temperature for 16 h, and then was quenched with satd aq NaHCO3 (5 mL). The aqueous layer was extracted with CHCl3 (10 mL), and the combined organic layers were dried (Na2SO4) and then concentrated under reduced pressure. The crude product was purified on silica gel (10 g; 0-10% methanol (2 M NH3)/CH2Cl2) to give 35 mg of the title compound (60%). MS (ESI): mass calculated for C16H23N5O, 301.39; m/z found, 302.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.11-11.07 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.37 (d, J=7.8 Hz, 1H), 4.80-4.65 (m, 2H), 3.92-3.78 (m, 2H), 2.56-2.53 (m, 4H), 2.36 (s, 3H), 1.85-1.81, (m, 1H), 1.32 (d, J=6.3 Hz, 6H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Li+].[N+:20]([CH3:23])([O-:22])=[O:21].C(OC(=O)C)(=O)C.C(N(CC)CC)C.[BH4-].[Na+]>O.CO.C(OCC)(=O)C>[N+:20]([CH2:23][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:14][CH:13]=1)([O-:22])=[O:21]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccccc2)nc1
Agent: C[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])CCc1ccc(COc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
To a methanol (20.0 mL) solution of 6-phenoxymethyl-pyridine-3-carbaldehyde (1.00 g, 4.69 mmol) described in Manufacturing Example 54-1-4 was added lithium methoxide (21.4 mg, 0.56 mmol) under nitrogen atmosphere at room temperature. This was cooled to 0° C., and nitromethane (372 mg, 6.10 mmol) and lithium methoxide (193 mg, 5.07 mmol) were added and stirred for 10 minutes at room temperature. The reaction solution was then concentrated under a reduced pressure. Tetrahydrofuran (20.0 mL) was added to the residue, and then acetic anhydride (6.24 g, 61.1 mmol) and triethylamine (1.42 mL, 10.2 mmol) were added and stirred for 1 hour at 70° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure. Methanol (20.0 mL) was added to the residue, and sodium borohydride (263 mg, 6.96 mmol) was then added on an ice bath (0° C.). Following 5 minutes of stirring at 0° C., water was added dropwise at 0° C. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (170 mg, 14.2%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[H-].[Na+].Cl[CH2:20][N:21]1[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][N:21]3[C:25]([Cl:26])=[C:24]([Cl:27])[N:23]=[CH:22]3)=[CH:12][CH:11]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(Oc2ccc(O)cc2)n1
Reactant: ClCn1cnc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(C)c(Oc2ccc(OCn3cnc(Cl)c3Cl)cc2)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
At room temperature (about 20° C.), 7.8 g of 4-(3,6-dimethyl-2-pyrazinyloxy)-phenol in 20 ml of anhydrous dimethylformamide is dripped into 1.3 g of 80% strength sodium hydride in 30 ml of anhydrous dimethylformamide. The mixture is stirred for one hour at 70° C., and then 6.68 g of 1-chloromethyl-4,5-dichloroimidazole in 30 ml of anhydrous dimethylformamide is dripped in. The mixture is stirred for 8 hours at 70° C. and overnight at room temperature. It is then stirred into 200 ml of ethyl acetate, and this mixture is washed twice with water, four times with 5% strength sodium hydroxide solution and twice with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The crude product obtained is crystallized with n-hexane. There is obtained 8.9 g of 1-[4-(3,6-dimethyl-2-pyrazinyloxy)-phenoxymethyl]-4,5-dichloroimidazole; m.p.: 84°-85° C.
Reaction SMILES: C(O[C:5]1([CH3:14])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH:12]=[CH2:13])(=O)C.[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>C(O)(=O)C>[C:15]([O:18][CH:9]1[CH2:8][C:7](=[O:10])[C:6]([CH2:11][CH:12]=[CH2:13])=[C:5]1[CH3:14])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: C=CCC1C(=O)C=CC1(C)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCC1=C(C)C(OC(C)=O)CC1=O
Yield: 176.3 %

Procedure:
Into a four necked flask equipped with an agitator and a thermometer, 3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (19.4 g), acetic acid (80 ml) and sodium acetate (4 g) were charged and refluxed for 5 hours with agitation. After the completion of the reaction, acetic acid was evaporated off under reduced pressure. The residue was shaken with toluene (70 ml) and water (40 ml). The organic layer was separated, washed with an aqueous solution of sodium bicarbonate and then water and concentrated. The residue was distilled to obtain 4-acetoxy-2-allyl-3-methyl-2-cyclopentenone (16.7 g). Yield, 86%. B.P., 100°-110° C./0.1-0.3 mmHg.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1>N1C=CC=CC=1>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1)=[O:8]
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ncc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of o-toluoyl chloride (17 g) in a few milliliters of pyridine was added dropwise to a suspension of 2-amino-5-nitrothiazole (16 g) in pyridine (100 ml), initially at room temperature, then at 0°. After the addition was complete, the reaction mixture was stirred for 2 hr at room temperature, and was then quenched in ice-water. Recrystallisation of the precipitated amide from 2-methoxyethanol afforded 2-methyl-N-(5-nitro-2-thiazolyl)benzamide, m.pt. 228°-230°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9](N(C)C2C=CC=CC=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[OH:19]S(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([OH:10])=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(C(=O)N(C)c2ccccc2)ccnc1Cl
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(C(=O)O)ccnc1Cl
Temperature: 130 °C
Yield: 54 %

Procedure:
2-chloro-N,3-dimethyl-N-phenylpyridine-4-carboxamide (2.2 g, 8.5 mmol) was treated with a mixture of concentrated H2SO4 (23.2 ml) and water (16.8 ml) and then heated to 130° C. for 46 hours. After which time, the reaction mixture was allowed to reach room temperature and poured onto ice (200 ml) and stirred until the ice had melted. The mixture was made alkaline (pH 8) by the addition of solid Na2CO3 (50.3 g) portionwise. The suspension was filtered and the filtrate acidified to pH 3 by the addition of 6M HCl (aq) (˜1.5 ml). The resulting solid was collected by filtration, washed with water (20 ml) and dried in-vacuo at 40° C. for 10 hours to give the title compound (779 mg, 54%) as a pink solid. LC-MS 100%, m/z=171.9, 173.9; 1H NMR (500 MHz, MeOD) δ ppm 8.30 (d, J=4.89 Hz, 1H) 7.64 (d, J=5.04 Hz, 1H) 2.58 (s, 3H).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[CH3:17][N:18]([CH3:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([N:18]([CH3:17])[CH3:28])[CH:20]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)c2cccc(N(C)C)c2)c(O)c1

Procedure:
Following the procedure described above in Example 58A, but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and m-dimethylaminobenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(m-dimethylaminobenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(m-dimethylaminobenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](=S)[NH:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[C:6]([NH:22][C:23](=[O:25])[CH3:24])[CH:5]=1)[CH3:2].C([N:29](C(C)C)CC)(C)C.CI.N.CO>C(#N)C>[NH2:29][C:18]1[S:19][C:15](=[CH:14][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[C:6]([NH:22][C:23](=[O:25])[CH3:24])[CH:5]=[C:4]3[O:3][CH2:1][CH3:2])[C:16](=[O:21])[N:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1cc(NC(C)=O)nc2ccc(C=C3SC(=S)NC3=O)cc12
Agent: N
Solvent: CO
Solvent: CC#N
Solvent: CI
Product: CCOc1cc(NC(C)=O)nc2ccc(C=C3SC(N)=NC3=O)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
A suspension of N-[4-ethoxy-6-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-quinolin-2-yl]-acetamide (example 6a, 80 mg, 0.21 mmol) in acetonitrile (3 ml) was reacted with diisopropylethyl amine (0.40 ml, 2.2 mmol) and methyl iodide (0.30 ml, 4.6 mmol) at rt for 30 min. The mixture was concentrated to dryness and the residue suspended in DMF (0.5 ml). A solution of ammonia in methanol (7N, 5 ml, 35 mmol) was added at rt, and the mixture was stirred at rt for 24 h. The mixture was concentrated to dryness and the solid was triturated with water. The precipitate was collected by suction filtration, successively washed with water and ether, and then air dried to afford the product as a light brown solid (50 mg, 663%). LC-MS m/e 357 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:10]1[N:11]=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccccn2)n[nH]1
Product: Clc1ccc(-c2ccccn2)nn1
Yield: 45 %

Procedure:
To a solid 6-pyridin-2-yl-2H-pyridazin-3-one (0.500 g, 2.900 mmol) was added 20 mL of POCl3 and the mixture was stirred at reflux for 4 hours. Excess POCl3 was removed in vacuo. The residue was poured on ice and neutralized using NaHCO3. The product was extracted with ether and ethyl acetate. The combined organic extracts were dried over MaSO4 and evaporated. The residue was purified by column chromatography to afford of 3-chloro-6-pyridin-2-ylpyridazine in 45% yield (0.250 g).
Reaction SMILES: [C:1]12[CH:7]([C:8]([OH:10])=O)[C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:13]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:8]([CH:7]3[C:4]4[CH2:5][CH2:6][C:1]3=[CH:2][CH:3]=4)=[O:10])[CH2:13]2)=[CH:20][CH:21]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(O)C1C2=CC=C1CC2
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1C2=CC=C1CC2

Procedure:
7-Norbornadienecarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-7-norbornadienecarboxamide.
Reaction SMILES: C(N(CC)C1C=CC=CC=1)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:27](=O)[NH:26][CH:25]=[N:24][C:23]=3[O:22][CH:21]=2)=[CH:16][CH:15]=1.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][C:27]1[C:28]2[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)=[CH:21][O:22][C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2coc3nc[nH]c(=O)c23)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc(-c2coc3ncnc(Cl)c23)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
Add 14.5 ml (13.6 g, 90.8 mmol) N,N-diethylaniline to a suspension of 10.0 g (41.3 mmol) 5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4(3H)-one in 250 ml toluene and heat to 100° C. At this temperature, add 4.2 ml (7.0 g, 45.4 mmol) phosphoryl chloride dropwise, and stir the reaction mixture for 15 h at 100° C. Then add a further 1.2 ml (2.0 g, 13 mmol) phosphoryl chloride and stir the reaction mixture again for 22 h at 100° C. After cooling to room temperature, quickly wash the reaction solution with, successively, 250 ml ice water, twice with 250 ml cold 20% sodium hydroxide solution each time, again with 250 ml ice water, 250 ml satd. sodium chloride solution, 1 N hydrochloric acid and 250 ml ice water. Dry the organic phase over sodium sulphate, filter and concentrate by vacuum evaporation. 6.3 g (59% of theor.) of the title compound is obtained.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH2:9]([O:11][C:12]([N:14]=[C:15]=[O:16])=[O:13])[CH3:10]>C(OCC)C>[CH3:7][O:6][C:4](=[O:5])[C:3]([C:15]([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[O:16])=[C:2]([NH2:1])[CH3:8]
Reactant: COC(=O)/C=C(/C)N
Reactant: CCOC(=O)N=C=O
Solvent: CCOCC
Product: CCOC(=O)NC(=O)C(C(=O)OC)=C(C)N
Reaction time: 4 h

Procedure:
To a solution of methyl 3-aminocrotonate (39.0 g, 0.339 mol) in anhydrous diethyl ether (200 mL) under nitrogen with magnetic stirring at 0-5° C. is added in dropwise fashion a solution of ethoxycarbonyl isocyanate (0.339 mol) in diethyl ether (40 mL). The resulting pale yellow colored suspension is stirred below 5° C. for 4 h. The solid is collected by suction filtration, rinsed with 50 mL of diethyl ether and dried under vacuum at room temperature for 30 h to obtain the title compound as an off-white solid.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:48](OCC)=[O:49])([CH2:32][C:33]2[C:38](Br)=[C:37]([O:40][CH3:41])[C:36]([O:42][CH3:43])=[C:35]([O:44][CH3:45])[C:34]=2[O:46][CH3:47])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>C(OCC)C.C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:32][C:33]3[C:38](=[C:37]([O:40][CH3:41])[C:36]([O:42][CH3:43])=[C:35]([O:44][CH3:45])[C:34]=3[O:46][CH3:47])[C:48]2=[O:49])=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
A hexane solution of n-butyl lithium (1.68 M, 11.3 ml, 19.0 mmols) was dropwise added to a THF (100 ml) solution of ethyl 2-(4-benzyloxyphenyl)-3-(6-bromo-2,3,4,5-tetramethoxyphenyl)-2-ethoxycarbonylpropionate (10.0 g, 15.8 mmols), under a nitrogen stream at −90° C or lower. The reaction mixture was stirred for 30 minutes, and a THF (10 ml) solution of acetic acid (1.86 g, 31.6 mmols) was dropwise added thereto still at −90° C. or lower. The reaction mixture was allowed to warm to room temperature, and diluted with diethyl ether. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain the entitled compound (3.78 g) as an oil.
Reaction SMILES: [OH-:1].[Na+:2].[O:3]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:11][C:10](=[O:12])[C:9]2([CH3:14])[CH3:13])=[CH:4]1>O1CCCC1>[Na+:2].[O:3]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]([CH3:14])([CH3:13])[C:10]([O-:1])=[O:12])[NH2:11])=[CH:4]1
Reactant: [OH-]
Reactant: CC1(C)C(=O)NC1c1ccoc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)[O-])C(N)c1ccoc1
Yield: 94.6 %

Procedure:
Sodium hydroxide (378 mg, 9.45 mmol) and tetrahydrofuran (10 ml) were added to 4-(3-furyl)-3,3-dimethyl-2-azetidinone (1.2 g, 7.21 mmol) and the mixture was refluxed for 8 hours. After the solvent was distilled off, the residue was washed with ethyl acetate to give a powder of β-(3-furyl)-α,α-dimethyl-β-alanine sodium salt (1.4 g, quant.).
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[BH:9]([OH:17])[O:10][CH:11](I)[CH2:12][CH:13]([F:15])[F:14].C[Si]([N-:22][Si](C)(C)C)(C)C.[Li+].[ClH:28].O1CCOCC1>C1COCC1>[OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[BH:9]([OH:17])[O:10][CH:11]([NH2:22])[CH2:12][CH:13]([F:15])[F:14].[ClH:28]
Reactant: OBOC(I)CC(F)F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC(CC(F)F)OBO
Temperature: -78 °C
Reaction time: 12 h

Procedure:
1-Iodo-3,3-difluoropropanyl boronate pinacol (2.7 g, 8.1 mmol) was dissolved in THF (10 mL) and was added dropwise to a solution of lithium bis(trimethylsilyl)amide (9.68 mL, 9.68 mmol, 1.0 M in THF) dissolved in anhydrous THF (10 mL) and cooled to −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. It was concentrated in vacuo and hexane was added. The reaction mixture was cooled to −78° C., followed by the dropwise addition of 4 N anhydrous hydrogen chloride in dioxane (6.05 mL, 24.2 mmol). The mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction mixture was evaporated and chloroform was added. Insoluble material was removed by filtration. The filtrate was evaporated almost to dryness and hexanes were added. Upon standing the product crystallized. It was isolated and washed with cold hexane to yield 1.1 g (52%), mp 138-141° C. 1H NMR (CDCl3) δ 7.68 (bs, 3H), 6.22-6.01 (tt, 1H), 3.42 (m, 1H), 2.76-2.51 (m, 2H), 1.32 (s, 12H). 19F NMR δ −115.2 to −115.5 (dt, CHF2). HRMS calculated for C9H18B1O2F2N+H: 222.1. Found: 222.1.
Reaction SMILES: [OH-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[S:13][C:12]([N:14]=CN(C)C)=[N:11][C:10]=1[CH3:19])=O.Cl.[CH3:22][C:23]1([C:26]([NH2:28])=[NH:27])[CH2:25][CH2:24]1.O>COCCO>[CH3:19][C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[C:7]1[CH:6]=[CH:5][N:28]=[C:26]([C:23]2([CH3:22])[CH2:25][CH2:24]2)[N:27]=1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Reactant: CC1(C(=N)N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: Cc1nc(N)sc1-c1ccnc(C2(C)CC2)n1
Temperature: 125 °C

Procedure:
Powdered sodium hydroxide (5.86 g) is added to a solution of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (13 g, prepared as described by S. Wang et al J. Med. Chem. 2004, 47, 1662-1675.) and 1-methyl-cyclopropanecarboxamidine hydrochloride (7.2 g, prepared as described in EP0227415) in 2-methoxyethanol (98 ml) and the mixture heated at 125° C. for 1 hour with stirring. The reaction mixture is cooled, water is added, and the title compound isolated by filtration. ESI-MS: M+H 247 and M−H 245.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH3:11][CH:12]([NH2:14])[CH3:13]>>[OH:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:14][CH:12]([CH3:13])[CH3:11])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)N
Reactant: O=C(O)C1CCC(O)CC1
Product: CC(C)NC(=O)C1CCC(O)CC1

Procedure:
Prepared as in Example 24a from 4-hydroxycyclohexanecarboxylic acid and propan-2-amine as a colorless oil (68%). MS 186 (MH+).