Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Br)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: [Na+]
Product: Cn1c(CC(=O)Nc2cccc(Br)c2)nc(N2CCOCC2)cc1=O
Yield: 17.2 %

Procedure:
The product is prepared according to the procedure described in Example 68, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 257 mg of 3-bromoaniline. 51 mg of N-(3-bromophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[S:12][CH:13]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[S:12][CH:13]=1
Reactant: CCOC(=O)c1cnn(-c2nc(-c3ccccc3OC)cs2)c1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc(-c3ccccc3O)cs2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of the title compound from Example 17 Step A (353 mg, 0.888 mmol) in DCM (6.3 ml) was added BBr3 (2.67 ml, 1.0 M in DCM, 2.67 mmol) dropwise. After the addition was complete, the mixture was allowed to warm up to ambient temperature. After 1 h, the reaction mixture was quenched by addition of sat. aq. NaHCO3 and extracted with DCM. The organic phase was separated and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 60% EtOAc in hexanes) provided the title compound as a yellow solid: LCMS m/z 384.5 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 10.17 (s, 1H), 8.18 (s, 1H), 7.67 (dd, J=8.0, 1.9 Hz, 1H), 7.34 (t, J=8.5 Hz, 1H), 7.09 (dd, J=8.2, 0.9 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 4.45 (m, 2H), 1.44 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:19]([C@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[O:40][C:41](=[O:44])[CH2:42]Br)[C@@H:35]1[C:30](=[CH:31][C:32](=[O:39])[CH2:33][CH2:34]1)[CH2:29][CH2:28]3)[CH3:20]>CC(C)=O.O>[CH2:19]([C@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[O:40][C:41](=[O:44])[CH2:42][O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:35]1[C:30](=[CH:31][C:32](=[O:39])[CH2:33][CH2:34]1)[CH2:29][CH2:28]3)[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CNC(=O)OC(C)(C)C
Yield: 89.2 %

Procedure:
In a mixture of 40 ml of acetone and 8 ml of water is dissolved 0.7 g of N-t-butoxycarbonylglycine, and 0.42 g of potassium t-butoxide is added to the solution. The mixture is stirred, followed by addition of 1.1 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 12 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is dissolved in a small amount of diisopropyl ether-n-hexane (1:1) and chromatographed on a silica gel column. Following passage of 100 ml of diisopropyl ether, elution is carried out with 400 ml of ethyl acetate. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.2 g of the above-identified compound as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][C:16](=[O:18])[CH3:17])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)ccc1Oc1ccccc1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a stirring compound of the title compound of Example 9 (5.0 g, 23 mmol) in pyridine (50 mL) was added acetic anhydride (2.75 g, 27 mmol), and the resulting solution was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in CHCl3 (300 mL) and extracted with HCl (1M, 3×150 mL), NaHCO3 (saturated, 3×150 mL), dried (MqSO4) and evaporated to yield an oil. The material was chromatographed (MPLC, 1:1 EtOAc:hexane) to yield 4.52 g of a yellow oil. This material was employed in Example 11 without further purication.
Reaction SMILES: [OH:1][CH:2]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH2:7][C@@H:6]1[C:19]([O-:21])=[O:20].[OH-].[Na+]>O1CCOCC1>[OH:1][CH:2]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH2:7][C@@H:6]1[C:19]([OH:21])=[O:20]
Reactant: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4ccsc4)C[C@@H]3C(=O)[O-])c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4ccsc4)C[C@@H]3C(=O)O)c2c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.73 g of methyl. (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-carboxylate, 7.6 cm3 of dioxane, and 1.22 cm3 of 5N aqueous sodium hydroxide solution was heated at a temperature in the region of 60° C. with stirring for 3 hours 30 minutes. After cooling to a temperature in the region of 20° C., the reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under argon pressure (55 kPa) on a column of silica gel (particle size 40-63 μm; diameter 5 cm; silica volume 120 cm3), elution was carried out first with 1120 cm3 of a dichloromethane/methanol/acetonitrile (92/8/7 by volume) mixture. Elution was subsequently carried out with 224 cm3 of the same mixture (but with a composition of 92/12/7 by volume), then 224 cm3 of the same mixture (with a composition of 92/16/7 by volume), then 400 cm3 of a dichloromethanel methanol (50/50 by volume) mixture, and finally 400 cm3 of pure methanol. A fraction of 112 cm3 was collected, followed by 7-cm3 fractions. Fractions 173 to 468 were combined and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 35° C. A foam was obtained, which foam was dried under reduced pressure (30 Pa) at a temperature in the region of 30° C. for 4 to 5 hours. 0.33 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a beige-colored solid with a foamy appearance melting at 113-115° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[N:9](C3CCCCO3)[N:8]=2)[C:3]1=[O:28]>Cl.O1CCOCC1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[NH:9][N:8]=2)[C:3]1=[O:28]
Reactant: CN1CCN(c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(c2n[nH]c3cnc(-c4cccnc4)cc23)C1=O
Yield: 15.5 %

Procedure:
A solution of 1-methyl-3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-2-one (0.140 g, 0.371 mmol) in 4.00 M of Hydrogen chloride in 1,4-Dioxane (3.00 mL) and 1,4-Dioxane (3.00 mL, 38.4 mmol) was stirred at RT for 18 h. The reaction was concentrated. The crude product was submitted HPLC to give 254 (16.9 mg, 15.4% yield). ESI MS m/z=295.1 (M+1). 1H NMR (400 MHz, DMSO) δ 9.18 (s, 1H), 9.04 (s, 1H), 8.82 (s, 1H), 8.56 (d, J=4.3 Hz, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.50 (dd, J=7.9, 4.7 Hz, 1H), 4.01-3.93 (m, 2H), 3.64-3.53 (m, 2H), 2.86 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=[O:21].CC(=CC)C.C([OH:31])(C)(C)C>>[C:20]([C:3]1[CH:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])([OH:31])=[O:21]
Reactant: COc1cccc2c1SC(c1ccccc1)C(C=O)=C2Cl
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Product: COc1cccc2c1SC(c1ccccc1)C(C(=O)O)=C2Cl

Procedure:
As in example 13 but starting from 3.16 g of 4-chloro-3-formyl-8-methoxy-thioflav-3-ene, 250 ml tert-butanol and 60 ml 2-methyl-2-butene. After work up the crude oil is crystallised in a mixture of n-hexane and ethyl acetate. Pure 3-carboxy-4-chloro-8-methoxy-thioflav-3-ene is obtained as yellow crystals; m.p. 207°-210° C.-TLC (SiO2, CH2Cl2 /Acetone/HCOOH 18/1/1): Rf =0.45.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[CH2:13]([O:1][C:2]1[C:9]([O:10][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 161.2 %

Procedure:
To a solution of 2,3-dihydroxybenzaldehyde (61, 25 g, 0.18 mol) in N,N-dimethylformamide (150 mL) tetrahydrofuran (250 mL), sodium hydride (7.24 g, 0.18 mol) was added at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 10 minutes. To the reaction mixture was then added benzyl bromide (54 mL, 0.45 mol). The reaction mixture was stirred at room temperature under an atmosphere of nitrogen for 3 hours, then cooled down to 0° C. Sodium hydride (8 g, 0.2 mol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (128, 46.2 gm, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][N:20]=3)[NH:14][C:13](=[O:28])[C:12]=2Cl)[CH:9]=1)[C:5]#[N:6].ClC1C(OC2C=C(C#N)C=C(Cl)C=2)=CC(/C=C/C2C3C(=NC=CC=3)N(C(OC(C)(C)C)=O)N=2)=NC=1OC>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][N:20]=3)[NH:14][C:13](=[O:28])[CH:12]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CCc3n[nH]c4ncccc34)[nH]c(=O)c2Cl)c1
Agent: COc1nc(/C=C/c2nn(C(=O)OC(C)(C)C)c3ncccc23)cc(Oc2cc(Cl)cc(C#N)c2)c1Cl
Product: N#Cc1cc(Cl)cc(Oc2cc(CCc3n[nH]c4ncccc34)[nH]c(=O)c2)c1

Procedure:
In a manner identical to that described above in Step 6 for Compound 3-8, from Compound 3-7 (325 mg; 0.604 mmol) was collected Compound 3-8 and the title compound 3-9 as a by product. MS M+1=391.8: 1H NMR (DMSO-d6): 2.90 (m, 2H), 3.20 (m, 2H), 5.75 (s, 1H), 7.12 (m, 1H), 7.20 (m, 1H), 7.55 (m, 1H), 7.64 (m, 2H), 8.20 (m, 1H), 8.45 (m, 1H), 12.30 (s, 1H), 13.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:12]([C:20]#[N:21])=[CH:11][C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1.ClC1C(C#N)=CC(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)N=1.C(N)C(C)C.C[Mg+].[Br-].[C:61](Cl)(=[O:64])[CH2:62][CH3:63]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:61](=[O:64])[CH2:62][CH3:63])[C:12]([C:20]#[N:21])=[CH:11][C:10]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: CC(C)CNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: CCC(=O)Cl
Agent: C[Mg+]
Agent: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: [Br-]
Solvent: CC(C)CN
Product: CCC(=O)N(CC(C)C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
To 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-(isobutylamino)pyridine-3-carbonitrile [prepared by reacting the product of Example 1 step C with isobutyl amine] (0.26 g) in TH (2.5 mL) was added MeMgBr (0.47 mL, 1.4 M solution in toluene THF 3:1) followed by propionyl chloride. After 1 hour 45 minutes the reaction was quenched with 2 M aqueous HCl, diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The dried solution (Na2SO4) was concentrated and purified via flash chromatography on silica gel eluted with 20% EtOAc in hexane affording the title compound. HPLC/MS: 486.2(M+1), 488.2 (M+3); Rt=4.60 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=[CH2:10])[CH:5]=[C:4]([CH:11]([OH:13])[CH3:12])[N:3]=1.[H-].[Na+].[CH3:16]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:16])=[C:6]([CH:9]=[CH2:10])[CH:5]=[C:4]([CH:11]([OH:13])[CH3:12])[N:3]=1
Reactant: C=Cc1cc(C(C)O)nc(Cl)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cc(C(C)O)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-vinyl-6-(1-hydroxyethyl)-pyridine (1.46 g, 7.31 mmol) in 12 mL of N,N-dimethylformamide is treated with sodium hydride (292 mg, 60% in oil, 7.31 mmol) and stirred at room temperature for 1 h. The mixture is treated with methyl iodide (0.5 mL, 8.04 mmol) and stirred for 2 h. The reaction is diluted with 125 mL of ethyl acetate and washed with 4×50 mL of saturated sodium chloride. The organics are dried over potassium carbonate and concentrated in vacuo. The crude material is chromatographed over 150 g of silica gel (230-400 mesh), eluting with 25% ethyl acetate/hexanes to give 1.09 g (78%) of 2-chloro-3-methoxy-4-vinyl-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>>[CH3:1][C:2]1[C:14]([CH3:15])=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c3c([nH]c2c1C)C(C(=O)O)CCC3
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Product: Cc1ccc2c([nH]c3c(C(=O)O)cccc32)c1C
Yield: 50 %

Procedure:
Under the conditions of Example 9, the ethyl ester of 7,8-dimethyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid is dehydrogenated with chloranil; after recrystallization from isopropyl alcohol, the ethyl ester of 7,8-dimethylcarbazole-1-carboxylic acid is obtained in a 50% yield, m.p. 92° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(Cl)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-chloroaniline
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.C(N(CC)C(C)C)(C)C.[C:40]([O:44][C:45](=[O:51])[NH:46][CH:47]1[CH2:50][NH:49][CH2:48]1)([CH3:43])([CH3:42])[CH3:41].O>CN1CCCC1=O>[C:40]([O:44][C:45](=[O:51])[NH:46][CH:47]1[CH2:50][N:49]([C:16]2[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=[C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])[N:6]=3)[N:15]=2)[CH2:48]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CN(c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)C1
Temperature: 150 °C
Yield: 69 %

Procedure:
150 mg (0.21 mmol, purity approx. 71%) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was dissolved, in a reaction vessel suitable for a microwave, in 1-methyl-2-pyrrolidone (3.1 ml), and 0.22 ml (1.24 mmol) of N,N-diisopropyl ethylamine and 143 mg (0.83 mmol) of tert.-butyl-azetidin-3-ylcarbamate were added. Then the reaction vessel was sealed with a septum and heated for 8 h at 150° C. in the microwave. Then 0.15 ml (0.82 mmol) of N,N-diisopropyl ethylamine and 107 mg (0.62 mmol) of tert.-butyl-azetidin-3-ylcarbamate were added again and the reaction mixture was heated for 3 h at 150° C. in the microwave. After cooling, water was added to the reaction mixture and it was purified by preparative HPLC (acetonitrile:water (+0.1% trifluoroacetic acid) gradient). 81 mg of the title compound was obtained (64% of theor.; purity 91%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[C@H:18]([CH3:19])[C@H:17]3[N:14]([C:15](=[O:23])[C@@H:16]3[C@H:20]([OH:22])[CH3:21])[C:13]=2[C:24]([O:26]CC=C)=[O:25])[CH2:8][N:7]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O.C(C(CCCC)C([O-])=O)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[H][H]>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[OH-].[Pd+2]>[F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[C@H:18]([CH3:19])[C@H:17]3[N:14]([C:15](=[O:23])[C@@H:16]3[C@H:20]([OH:22])[CH3:21])[C:13]=2[C:24]([OH:26])=[O:25])[CH2:8][NH:7]1
Reactant: [H][H]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCF)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (4.00 g), sodium 2-ethylhexanoate (1.21 g), and triphenylphosphine (0.35 g) in tetrahydrofuran (120 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.77 g) at ambient temperature in a stream of nitrogen. The mixture was stirred at the same condition for one hour. To the mixture was added 0.1M phosphate buffer (pH 6.0) (120 ml). The mixture was stirred in the presence of 20% palladium hydroxide on carbon (0.8 g) under atmospheric pressure of hydrogen at ambient temperature for 4 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to remove the tetrahydrofuran. An aqueous solution was washed with ethyl acetate (100 ml×3) and the organic solvent was removed by evaporation. The residual solution was subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (100 ml) and eluted with a mixture of acetone and water (7:93 V/V). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid as a solid (1.36 g). ##STR31##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu].[Cu]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:21]3[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=3[C:23]([OH:25])=[O:24])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Reactant: O=C(O)c1ccccc1Cl
Agent: Cl[Cu]
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(CCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1OC
Yield: 33.3 %

Procedure:
The title compound was prepared from 4-[2-(3,4-dimethoxy-phenyl)-ethyl]phenylamine (9.25 g, 0.036 mol), 2-chlorobenzoic acid (5.2 g, 0.036 mol), anhydrous potassium carbonate (15.0 g, 0.11 mol), copper powder (0.45 g, 0.007 mol), and a catalytic amount of copper(I) chloride in dry DMF (75 mL) using the procedure described in Example 1, Step C, Method B. After crystallization with MeOH/H2O, 4.5 g (0.012 mol, 33%) of the desired product was obtained mp: 137-139° C.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:4][C:3]1([CH3:8])[C:5](O)=[O:6].S(Cl)([Cl:12])=O>>[F:1][C:2]1([F:9])[CH2:4][C:3]1([CH3:8])[C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC1(C(=O)O)CC1(F)F
Product: CC1(C(=O)Cl)CC1(F)F
Yield: 77 %

Procedure:
A mixture of 250 g (1.8 mol) of 2,2-difluoro-1-methylcyclopropanecarboxylic acid and 700 ml of thionyl chloride is slowly heated in a distillation apparatus, during which process excess thionyl chloride distills over first and the desired product later. In this manner, 215 g (77% of theory) of 2,2-difluoro-1-methyl-cyclopropanecarbonyl chloride are obtained in form of a liquid of boiling point 121°-122° C. ##STR56##
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[Cl:21][S:22](O)(=[O:24])=[O:23]>>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([S:22]([Cl:21])(=[O:24])=[O:23])[CH:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1cccc2c1CCCC2
Reactant: O=S(=O)(O)Cl
Product: Cc1ccccc1C(=O)Nc1cc(S(=O)(=O)Cl)cc2c1CCCC2
Temperature: 25 °C

Procedure:
To neat amide (58), at 0° C., was added chlorosulfonic acid (5 eq) dropwise. The temperature was allowed to warm to 25° C. and then heated at 70° C. for 45 minutes. After cooling to 25° C., the reaction mixture was poured into ice water, and the resultant precipitate was collected by filtration to give the title compound as a solid. The product (mixture of regioisomers) was used without further purification.