Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:48]2[CH2:53][CH2:52][CH:51]([N:54]3[CH2:59][CH2:58][N:57]([S:60]([CH3:63])(=[O:62])=[O:61])[CH2:56][CH2:55]3)[CH2:50][CH2:49]2)=[CH:41][C:42]([O:46][CH3:47])=[C:43]([CH:45]=1)[NH2:44])[CH3:38].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]3[CH:45]=[C:39]([CH2:37][CH3:38])[C:40]([N:48]4[CH2:49][CH2:50][CH:51]([N:54]5[CH2:55][CH2:56][N:57]([S:60]([CH3:63])(=[O:62])=[O:61])[CH2:58][CH2:59]5)[CH2:52][CH2:53]4)=[CH:41][C:42]=3[O:46][CH3:47])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(CC)c(N4CCC(N5CCN(S(C)(=O)=O)CC5)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 170 °C
Yield: 70.1 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.125 g, 0.247 mmol), 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.098 g, 0.247 mmol) and HCl (4N,1,4-Dioxane, 0.12 mL, 0.494 mmol) in trifluoroethanol (8 mL) was heated at 170° C. for 40 min in the microwave. The reaction was quenched with 7 N NH3 in MeOH and then concentrated to dryness. The residue was then dissolved in DCM and concentrated onto silica gel. Purification by flash column chromatography followed by recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamide (0.150 g, 67%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.30-9.43 (m, 1H), 8.50 (s, 1H), 8.25 (d, J=5.22 Hz, 1H), 8.06 (d, J=2.02 Hz, 1H), 7.74-7.80 (m, 1H), 7.71 (d, J=8.89 Hz, 1H), 7.53 (s, 1H), 7.34-7.49 (m, 2H), 7.28 (d, J=8.43 Hz, 1H), 7.16-7.25 (m, 2H), 6.91-7.00 (m, 1H), 6.83 (s, 1H), 6.58 (d, J=5.04 Hz, 1H), 4.20-4.33 (m, 2H), 3.81 (s, 3H), 3.08-3.16 (m, 4H), 3.00-3.08 (m, 2H), 2.88 (s, 3H), 2.67-2.78 (m, 2H), 2.61-2.66 (m, 4H), 2.56 (q, J=7.51 Hz, 2H), 2.38-2.47 (m, 1H), 1.79-1.92 (m, 2H), 1.52-1.68 (m, 2H), 1.44 (t, J=6.92 Hz, 3H), 1.11 (t, J=7.51 Hz, 3H). MS (M+H, ES+) 866.
Reaction SMILES: Cl[C:2]([F:8])([F:7])C(OC)=O.[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:7][CH:2]([F:8])[O:17][C:16]1[CH:18]=[CH:19][C:11]([CH:10]=[O:9])=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OC(F)F
Temperature: 67.5 °C
Yield: 40.5 %

Procedure:
Methyl chlorodifluoroacetate (1.4 mL, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 mL). The suspension was heated to 65-70° C. for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10% EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41%) as a colourless oil; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J=74 Hz, 1H, OCHF2), 7.30 (d, J5,6=8.0 Hz, 1H, H5), 7.45 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.50 (d, J2,6=2.0 Hz, 1H, H2), 9.93 (s, 1H, CHO); δC (100 MHz, CDCl3) 56.2, 110.9, 115.5 (t, J=256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>O>[CH3:18][O:19][CH2:20][CH2:21][O:22][CH2:2][C:3](=[CH2:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=C(COCCOC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(bromomethyl)acrylate (2.0 g, 9.0 mmol) in 2-methoxyethanol (30 ml) at 0° C. was added, in one portion, potassium carbonate (2.5 g, 18 mmol) and the mixture stirred at 0° C. for 1 hour. The reaction was diluted with distilled water (100 ml) and extracted with dichloromethane (100 ml). The layers were separated and the aqueous layer further extracted with dichloromethane (2×50 ml). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica by eluting with hexane/ethyl acetate (2:1) to give, after combination and evaporation of appropriate fractions, the title compound as a yellow oil, (1.6 g, 82%). Rf. 0.32 (silica, hexane/ethyl acetate, 2:1). 1H-NMR (300 MHz, CDCl3) 1.50 (s, 9H), 3.42 (s, 3H) , 3.56-3.63 (m, 2H), 3.65-3.74 (m, 2H), 4.25 (s, 2H), 5.84 (s, 1 H), 6.25 (s, 1H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.C1COCC1>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:20])=[O:3])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)CC1CCN(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (1.38 g) obtained in the above (2) is dissolved in a mixture of methanol (20 ml) and THF (10 ml), and thereto is added an aqueous sodium hydroxide solution (NaOH; 2.1 g, water; 10 ml), and the mixture is stirred at room temperature for 30 minutes. The pH value of the mixture is adjusted to pH 1 with conc. hydrochloric acid, and the reaction mixture is concentrated under reduced pressure. To the residue is added isopropanol, and the mixture is stirred at room temperature for one hour, and the precipitates are removed by filtration. The filtrate is concentrated under reduced pressure to give the title compound (1.20 g) as a powder.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[C:12]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[C:12]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]=1)[C:5]([Cl:21])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C(C(=O)O)c1csc2cccc(Cl)c12
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CON=C(C(=O)Cl)c1csc2cccc(Cl)c12

Procedure:
α-Methoxyimino-α-(4-chloro-3-benzothienyl)acetic acid was reacted with oxalyl chloride and N,N-dimethylformamide in benzene to give α-methoxyimino-α-(4-chloro-3-benzothienyl)acetyl chloride. A solution of 1.47 g (5.45 mM) of the acid chloride in 30 ml of acetone was added dropwise over ten minutes to a cold (5° C.) stirred solution of 1.22 g (5.7 mM) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 30 ml of water and 30 ml of acetone containing 1.37 g (16.35 mM) of sodium bicarbonate. The reaction mixture was stirred at 0°-5° C. for thirty minutes following the addition, and then was warmed to 20° C. and stirred for an additional two hours. The reaction mixture was concentrated to a volume of about 30 ml, diluted with 20 ml of water, and washed several times with ethyl acetate. The aqueous mixture was layered with 50 ml of fresh ethyl acetate and acidified to pH 2.5 by addition of 1N hydrochloric acid. The organic layer was separated, washed with fresh water and with brine, dried and the solvent was removed by evaporation to give 2.1 g (83% yield) of 7-[α-methoxyimino-α-(4-chloro-3-benzothienyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. NMR (DMSOd6): δ 2.03 (s, 3H); δ 3.51 (broad s, 2H); δ 3.98 and 4.10 (two singlets, 3H); δ 5.11 (d, 1H); δ 5.68 (dd, 1H); δ 7.3-8.1 (m, 4H); δ 8.78 and 8.95 (two d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([CH:10]2[O:14][CH:13]([CH2:15][O:16]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)[CH:12]([OH:40])[CH2:11]2)[CH:3]=1.[Si:41](Cl)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N1C=CN=C1>CN(C=O)C>[Si:41]([O:40][C@@H:12]1[C@@H:13]([CH2:15][OH:16])[O:14][C@@H:10]([N:4]2[CH:3]=[C:2]([CH3:1])[C:8](=[O:9])[NH:7][C:5]2=[O:6])[CH2:11]1)([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5′-O-Dimethoxytritylthymidine is silylated with 1 equivalent of t-butyldiphenylsilyl chloride (TBDPSC1) and 2 equivalents of imidazole in DMF solvent at room temperature. The 5′-protecting group is removed by treating with 3% dichloracetic acid in CH2Cl2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].Cl>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:12]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:23](=[O:24])[NH:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CCN[C@@H](CN)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CCN2C(=O)NC[C@H]2c2ccc(OC)cc2)cc1
Yield: 96.9 %

Procedure:
A solution of 1-(R)-(4-methoxyphenyl)-N1-[2-(4-methoxyphenyl)ethyl]ethane-1,2-diamine (446 g, 1.48 mol) in ethyl acetate (2.25 L) is placed in a water bath and 1,1′-carbonyldiimidazole (264 g, 1.62 mol) is added in portions. The reaction is then heated to reflux for 1.5 hours after which the solution is cooled, treated with 1N HCl (2×1.5 L), brine (2×1.5 L), dried over Na2SO4 and set aside in the cold. After standing the precipitate which forms is removed by filtration and the solvent removed under reduced pressure to afford 468 g (96% yield) of the desired product. Chiral HPLC of the product thus obtained to have 99.5% of the desired (R) enantiomer present.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([C:15]3(O)[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)=[C:10]([F:22])[CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[S:18]1[CH2:17][CH:16]=[C:15]([C:11]2[C:12]([F:14])=[CH:13][C:8]([N:3]3[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]3[CH3:7])=[CH:9][C:10]=2[F:22])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C)n1-c1cc(F)c(C2(O)CCSCC2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C)n1-c1cc(F)c(C2=CCSCC2)c(F)c1

Procedure:
A stirred solution of 4-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2,6-difluorophenyl]tetrahydro-2H-thiopyran-4-ol (Step 2, 1.617 g, 5.00 mmol) and p-toluenesulfonic acid monohydrate (0.107 g) in benzene (20 mL) is heated at reflux using a Dean-Stark trap for 5 h, during which additional p-toluenesulfonic acid monohydrate (0.342 g) is added. Solvent is then removed under reduced pressure, and the residue is taken up in CH2Cl2 (60 mL), washed with saturated aqueous NaHCO3 (2×20 mL) and water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge, eluting with 2-5% EtOAc/Hexanes, affords the title compound, mp 118-119° C.; MS (ESI+) for C17H17F2NS m/z 306 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[N+:18]([O-])=O.[Cl-].[NH4+]>[Zn].CC(C)=O.O>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:6]=1[NH2:18]
Reactant: CN(C)C(=O)Sc1ccc(Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=O)Sc1ccc(Cc2ccccc2)cc1N
Reaction time: 4 h

Procedure:
To a solution of S-4-benzyl-2-nitrophenyl dimethylcarbamothioate (1.58 g, 4.99 mmol) in 25 mL 5:1 acetone/water under nitrogen was added zinc, nanosize activated powder (1.63 g, 25.0 mmol) and ammonium chloride (2.67 g, 49.9 mmol). The reaction became hot and was cooled with an ice bath. The heterogeneous reaction was allowed to stir for ˜4 h. The reaction was allowed to stand overnight and was partitioned between 200 mL EtOAc and water. The organic layer was washed with brine, and dried over sodium sulfate, filtered, and concentrated to give S-2-amino-4-benzylphenyl dimethylcarbamothioate which was used without further purification. MS (ESI) m/z: Calculated: 286.1; Observed: 287.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=O)[O:28]C(C)(C)C)[CH3:25])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.Cl.[C:35](OCC)(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:28])[CH3:35])[CH3:25])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (1.09 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (640 mg). 1H NMR (300 MHz, CDCl3) δ 0.39-0.49 (2H, m), 0.63-0.75 (2H, m), 1.28-1.43 (4H, m), 2.02 (3H, s), 3.95-4.09 (4H, m), 4.36-4.50 (1H, m), 5.74 (1H, d, J=8.3 Hz), 6.95 (1H, dd, J=8.9, 2.5 Hz), 7.00 (1H, d, J=8.7 Hz), 7.11 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.7 Hz), 8.04 (1H, dd, J=8.7, 1.9 Hz), 8.22 (1H, d, J=1.9 Hz).
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[NH:6][CH:7]=1.[OH-].[NH4+:24]>>[C:2]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[NH:6][CH:7]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(F)(F)F)c[nH]2)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C#N)c[nH]2)CC1
Temperature: 60 °C
Yield: 83 %

Procedure:
Combine tert-butyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1.50 g, 4.70 mmol) and ammonium hydroxide (90 mL). Heat the reaction mixture at 60° C. for two days. Let cool to room temperature, then filter via Buchner funnel Wash the solids with water and hexanes to give the title compound as a white solid (1.08 g, 83%). MS (ES) m/z=221 [M]+.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=O)[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][C:4]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[N:2][CH3:1])[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: CN
Reactant: Cc1cc2ccncc2c(=O)c2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CN=c1c2cnccc2cc(C)c2ccccc12
Reaction time: 4 h

Procedure:
A solution of titanium tetrachloride (0.7 ml., 0.006 mole) in benzene (20 ml.) is added rapidly to a stirred solution of methylamine (1.24 g., 0.04 mole) and 6-methylbenzo[5,6]cyclohepta[1,2-c]pyridin-11-one (2.21 g., 0.01 mole) in benzene (150 ml.). After 4 hours, anhydrous potassium carbonate is added and the reaction mixture is filtered. The filtrate is evaporated to a pale yellow oil, (2.95 g.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]([CH3:17])=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[C:19](OC(=O)C)(=O)[CH3:20]>C(O)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[C:5]([CH3:17])[N:4]=[C:3]([CH3:18])[C:2]=3[N:1]=[C:19]2[CH3:20])=[CH:10][CH:11]=1)#[N:16]
Reactant: Cc1cc(Nc2ccc(C#N)cc2)c(N)c(C)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(nc(C)n2-c2ccc(C#N)cc2)c(C)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 3-amino-4-(4-cyanophenyl)amino-2,6-dimethyl-pyridine (4.20 g, 17.6 mmol), acetic anhydride (12.6 ml) and acetic acid (12.6 ml) was stirred at 100° C. for 16 hours. The excess of reagents was removed under reduced pressure, and the residual gum was dissolved in water and the solution was rendered basic by the addition of concentrated aqueous ammonia. The white solid which precipitated was filtered off and dried in vacuo to give the title compound (4.06 g, 88%), mp 260°-262° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].CS([C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)=O>O1CCCC1>[OH:4][CH2:3][CH2:2][S:1][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCCS
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1N[C@H](SCCO)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Under ice-cooling, 2.58 g of 2-mercaptoethanol and 33 ml of 1N sodium hydroxide are added to a solution of 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone in 150 ml of tetrahydrofuran, and the mixture is stirred for 30 minutes. The solvent is then distilled off under reduced pressure and 150 ml of ethyl acetate is added. The ethyl acetate layer is separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography using ethyl acetate-n-hexane (1:2). The earlier eluate fractions are combined and concentrated under reduced pressure to give 5.6 g of (3R,4R)-4-[[2-(hydroxy)ethyl]thio]-3-tritylamino-2-azetidinone.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=2[N:5]2[N:13]=[C:14]([CH3:16])[CH:15]=[C:4]2[N:3]=1.[Na].[CH2:18]([OH:20])[CH3:19]>>[Cl:12][C:10]1[N:9]=[CH:8][C:7]2[C:2]([O:20][CH2:18][CH3:19])=[N:3][C:4]3[N:5]([N:13]=[C:14]([CH3:16])[CH:15]=3)[C:6]=2[CH:11]=1
Reactant: CCO
Reactant: Cc1cc2nc(Cl)c3cnc(Cl)cc3n2n1
Agent: [Na]
Product: CCOc1nc2cc(C)nn2c2cc(Cl)ncc12
Reaction time: 1 h

Procedure:
2.5 g. of 5,8-dichloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine are added to a solution of 0.3 g. sodium in 20 ml. of ethanol. The mixture is stirred at 60° for 1 hour. After addition of 10 ml. of water, 8-chloro-5-ethoxy-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine precipitates and is filtered off, yield: 1.8 g. (68%); m.p. 175.6° (ethyl acetate).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22]Br)=[CH:19][CH:18]=1.[OH-].[Na+]>CO>[F:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc(-c2cn(CCc3ccc(F)cc3)cn2)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and 4-fluorophenethyl bromide according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH. 1HNMR (400 MHz, DMSO): δ 3.09 (2H, t, J=7.1 Hz), 4.27 (2H, t, J=7.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.24 (2H, t, J=7.1 Hz), 7.57 (1H, d, J=3.8 Hz), 7.63 (1H, s), 7.82 (1H, s), 8.26 (1H, s), 8.63 (1H, d, J=5.0 Hz). [M+H] Calc'd for C17H14FN3O2, 312. Found, 312.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:16]([O:15][C:11]([CH2:12][CH2:13][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: N#CCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(CC#N)cc1
Reaction time: 72 h

Procedure:
A mixture of 5 g of p-bromophenylacetonitrile, 4.6 ml of t-butyl acrylate, 57 mg of palladium diacetate, 310 mg of tri-o-tolylphosphine and 12 ml of triethylamine is refluxed for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with 10% HCl and saturated sodium bicarbonate solution. After drying over magnesium sulfate the solvent is removed in vacuo. This material is dissolved in ethanol and hydrogenated over 1.1 g of 10% palladium on carbon catalyst for 3 days at 3 atmospheres pressure of hydrogen. After filtration the solvent is removed in vacuo and the residue is chromatographed on silica gel with ether/hexane (1:1) as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-phenylacetonitrile; 2.8 g of this product is dissolved in 90 ml of tetrahydrofuran and 50 ml of methanol and to this is added 6.2 g of cobalt chloride in 90 ml of water followed by 2.1 g of sodium borohydride in small portions. After filtration and removal of solvent, the residue is chromatographed on silica gel with 7.5% methanol saturated with ammonia in methylene chloride as the eluent to afford p-(2-t-butoxycarbonyl-ethyl)-2-phenethylamine as an oil.