Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([NH:12][C:13](=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].P(Cl)(Cl)(Cl)=O>ClCCCl>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][C:13]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])[N:12]=1
Reactant: CCOC(=O)C(NC(=O)Cc1ccccc1F)c1ccccn1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cc2ccccc2F)n2ccccc12

Procedure:
2.72 g (8.60 mmol) of ethyl {[(2-fluorophenyl)acetyl]amino}(pyridin-2-yl)acetate from example 6A are introduced into 30 ml of 1,2-dichloroethane, and 4.81 ml (51.6 mmol) of phosphoryl chloride are added. The mixture is heated to reflux for 9 h and then concentrated in vacuo, and the residue is taken up in ethyl acetate. The solution is washed with saturated sodium carbonate solution, dried over sodium sulfate and purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1). 2.16 g (84% of theory) of the desired compound are obtained as a dark oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH3:22])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][CH:12]=2.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:23][CH2:22][C:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:19])[F:20])[N:10]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc2nc(CBr)c(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-(2-Chlorophenyl)-2-methyl-5-(trifluoromethyl)quinoxaline (0.9969 g, 3.089 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.5299 g, 1.853 mmol) were suspended in carbon tetrachloride (30.89 mL, 3.089 mmol). To the mixture was added benzoyl peroxide (0.09977 g, 0.3089 mmol) and the mixture was heated at reflux. After 20 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 5% gradient of EtOAc in hexane over 10 min, then 5% isocratic of EtOAc for 30 min, then 5 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-3-(2-chlorophenyl)-5-(trifluoromethyl)-quinoxaline as an off-white syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (1H, dd, J=8.6, 0.8 Hz), 8.37 (1H, d, J=6.7 Hz), 8.09 (1H, t, J=7.8 Hz), 7.55-7.77 (4H, m), 4.73 (2H, d, J=61.8 Hz); LC-MS (ESI) m/z 403.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])(O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O>CCO>[C:20]1([C:19]2[C:18]3[C:13](=[C:14]([C:26]([F:29])([F:27])[F:28])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH2:8])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(O)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 84.6 %

Procedure:
1-phenyl-1-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]ethanol (0.675 g, 1.72 mmol) in EtOH (13 mL) is refluxed with conc HCl (2.6 mL) for 2 h. The cooled reaction is poured into water and extracted with methylene chloride. The extract is washed with saturated aq sodium bicarbonate, dried (MgSO4) and concentrated. The residue is chromatographed eluting with 5:95 ethyl acetate:hexane to afford the title compound as a yellow solid (0.546 g, 85%). MS (ESI) m/z 376; HRMS: calcd for C24H16F3N+H, 376.13131; found (ESI, [M+H]+), 376.1306.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:13][C:14](=O)[C@H:15]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:46]2)=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[N:13]=[C:14]([C@H:15]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[S:46][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:36]
Reactant: COC(=O)C(NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc([C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)sc1-c1ccccc1
Yield: 72.9 %

Procedure:
2-((2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionylamino)-3-oxo-3-phenylpropionic acid methylester (2.2 g; 4.069 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (4.1 g; 10.17 mmol) were refluxed 6 hours in 50 ml tetrahydrofuran. The solvent was removed in vacuo and the residue was chromatographed on silica; (4×40 cm) using ethyl acetate/heptane (1:1) as eluent and the residue was recrystallised from ethyl acetate/heptane (1:1; 50 ml) to afford 1.45 g of 2-((1R)-1-(tert-butoxycarbonylamino)-2-(2-naphthyl)-ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid methylester.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1.O.[NH2:24][NH2:25]>CO>[NH:24]([C:3](=[O:2])[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1)[NH2:25]
Reactant: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of benzyl 4-(2-methoxy-2-oxoethoxy)benzoate (1.0 g, 3.33 mmol) in MeOH (15 mL) was added hydrazine hydrate (1.7 mL). After stirring for 1 h at rt, the reaction mixture was filtered. The cake was washed with MeOH (3×4 mL) and dryed under vacuo at 50° C. overnight gave 936 mg of the title compound (94%) as a white solid in 99.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:18])[CH:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>ClCCCl>[OH:18][C:4]1[CH2:5][CH:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:7][C:2](=[O:1])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: O=C1C=C(O)CC(c2cccc3ccccc23)C1
Solvent: ClCCCl
Product: CCC(=O)C1=C(O)CC(c2cccc3ccccc23)CC1=O

Procedure:
Stannic chloride (12.0 g) was added dropwise to a mixture of 3-hydroxy-5-(naphth-1-yl)cyclohex-2-en-1-one (10 g) and propionyl chloride (4.25 g) in 1,2-dichloroethane (50 ml). the mixture was stirred and heated at reflux under nitrogen for 6 hr. After cooling, the mixture was poured onto ice. The dichloromethane extract was evaporated and the residue was heated at reflux with a 2M sodium hydroxide solution (20 ml) for 2 hr. After cooling, the solution was poured into an ice/hydrochloric acid mixture. The dried (Na2SO4) dichloromethane extract was concentrated and the residue was purified by column chromatography over silica gel with dichloromethane elution to give 3-hydroxy-5-(naphth-1-yl)-2-propionylcyclohex-2-en-1-one as a white solid.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1Br>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[C:3]([CH:19]1[CH2:18][CH2:17][CH:16]=[CH:15]1)([CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Br[C@@H]1CCC[C@H]1Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C(=O)OCC)C1C=CCC1
Reaction time: 3 h

Procedure:
52.4 g of sodium, cut into small pieces, was introduced into a three-necked flask equipped with dropping funnel, reflux condenser, and KPG agitator. Under an argon atmosphere, 790 ml of absolute ethanol was added dropwise thereto within 3 hours so that the reaction mixture was boiling vigorously. Within 1.5 hours, 157 g of diethyl methylmalonate was added dropwise to the hot, slightly turbid alcoholate solution. The mixture was agitated for another hour and then 205 g of trans-1,2-dibromocyclopentane was added dropwise within one hour to the cooled-off solution. Thereafter the solution was refluxed for 17 hours. After concentration of the reaction solution on a forced circulation evaporator, the residue was combined with ether and dilute hydrochloric acid, the organic phase was washed neutral with saturated sodium chloride solution, dried over sodium sulfate, and distilled under vacuum, thus obtaining 170 g, bp1.5 90°-105° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2=[N:33][CH:34]=[N:35][C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][O:53][Si](C(C)C)(C(C)C)C(C)C)[C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][N:43]=3)=[O:40])=[C:31]2[CH:30]=[N:29]1>O1CCCC1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[C:21]=1[N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:37][C@@H:38]([CH2:49][O:50][C@H:51]([CH3:64])[CH2:52][OH:53])[C:39]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][N:43]=3)=[O:40])[C:31]=2[CH:30]=[N:29]1
Reactant: CC(C)[Si](OC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1C#N)C(=O)Nc1ccc(Cl)cn1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)OC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1C#N)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (0.891 mL, 0.89 mmol) was added in one portion to a stirred solution of (2S)-2-(1-(2-chloro-6-cyanophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-chloropyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AY1) (610 mg, 0.89 mmol) in tetrahydrofuran (15 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (10 mL), and diluted with water (20 mL) and EtOAc (70 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (70 mL), The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 80% EtOAc in isohexane to afford the product (281 mg, 59.7%). 1H NMR (400 MHz, DMSO) δ 1.07 (3H, d), 3.33 (1H, q), 3.40-3.46 (1H, m), 3.61-3.69 (1H, m), 4.09-4.16 (2H, m), 4.57 (1H, t), 5.90 (1H, s), 7.87-7.91 (2H, m), 8.01-8.05 (1H, m), 8.16-8.19 (2H, m), 8.40-8.41 (1H, m), 8.61 (1H, s), 8.78 (1H, t), 11.17 (1H, d); m/z (ES−) (M−H)−=526; HPLC tR=2.94 min.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O)([CH3:9])[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6].[NH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:22]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:21]([NH:20][CH2:15][C:14]2[CH:17]=[C:10]([C:2]([CH3:9])([CH3:1])[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6])[CH:11]=[CH:12][C:13]=2[O:18][CH3:19])[C@@H:22]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COC(=O)C#CC(C)(C)c1ccc(OC)c(C=O)c1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: COC(=O)C#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 59 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [CH:1]([C:3]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:5]([O:6][C:7]3=O)[CH2:4]1)[CH2:11]2)=[CH2:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:3]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:5]([O:6][C:7]3=[S:24])[CH2:4]1)[CH2:11]2)=[CH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=CC12CC3CC(C1)OC(=O)C(C3)C2
Solvent: Cc1ccccc1
Product: C=CC12CC3CC(C1)OC(=S)C(C3)C2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a mixture of 6-vinyl-3-oxatricyclo[4.3.1.14,8]undecan-2-one (10 mmol) obtained by the procedure of Example 3 and toluene (50 ml) was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide [(p-MeO-C6H4P(═S)—S—)2)] (10 mmol), and the resulting mixture was stirred at 110° C. for 24 hours. The reaction mixture was concentrated, the concentrate was subjected to silica gel column chromatography and thereby yielded the title compound 6-vinyl-3-oxatricyclo[4.3.1.14,8]undecane-2-thione in a yield of 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:11]1[C:2]([NH:1][S:40]([C:37]2[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:45])=[CH:39][CH:38]=2)(=[O:42])=[O:41])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[O:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1

Procedure:
Analogously to Example 77, by condensing methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate with 4-(trifluoromethyl)-benzenesulphonyl chloride there was obtained methyl 4-(2-chloro-5-methoxy-phenoxy)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5-(4-trifluoromethyl-benzenesulphonylamino)-benzoate and therefrom by treatment with 5.5M HCl there was obtained methyl 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-trifluoromethyl-benzenesulphonylamino)-benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1)[NH2:15]
Reactant: NN
Reactant: Clc1cc(-c2ccccn2)ccn1
Solvent: c1ccncc1
Product: NNc1cc(-c2ccccn2)ccn1

Procedure:
A mixture of 5.0 g of 2'-chloro-2,4'-bipyridine, 5 ml of anhydrous hydrazine and 100 ml of pyridine was refluxed. Additional 5 ml portions of anhydrous hydrazine were added after 18, 36 and 54 hours of refluxing. The solution was then refluxed for an additional 48 hours and the solvent removed under vacuum. The solid was dissolved in methylene chloride, treated with activated carbon, filtered and the filtrate concentrated to dryness. The residue was triturated with hexane, giving crystals which were recrystallized from methylene chloride-hexane, giving 2'-hydrazino-2,4'-bipyridine as yellow crystals, mp 120°-121° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH:67]1[CH2:72][CH2:71][N:70]([C:73](=[O:75])[CH3:74])[CH2:69][CH2:68]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[C:73]([N:70]1[CH2:71][CH2:72][CH:67]([NH:66][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:68][CH2:69]1)(=[O:75])[CH3:74]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(C)=O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.12 mmole) of 1-(4-Amino-piperidin-1-yl)-ethanone was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.05 g of N-(1-acetyl-piperidin-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-102) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][O-:34].[Na+]>CO.C(OCC)(=O)C>[CH3:33][O:34][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
To a solution of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188, 15 mg, 0.03 mmol) in methanol (1 mL) was added sodium methoxide solution (5.4M solution in methanol, 11 uL, 0.06 mmol) and the reaction mixture was then stirred at 90° C. for 16 h. The reaction mixture was concentrated in vacuo to give a crude residue which was diluted with ethyl acetate and washed with water, sat.NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography to yield the desired product as a white solid (14 mg, 94%). MS (ESI): 486.3 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:12]([C:14]([OH:16])=O)[CH3:13])=[CH:3]1.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:38]([NH2:42])([CH3:41])([CH3:40])[CH3:39]>C1C=CC=CC=1.C(Cl)Cl.CCCCCC>[CH3:39][C:38]([NH:42][C:14]([CH:12]([C@@H:11]1[C@:17]2([CH3:25])[C@H:8]([C@H:7]3[C@H:20]([CH2:19][CH2:18]2)[C@:21]2([CH3:24])[C:4](=[CH:3][C:2](=[O:1])[CH2:23][CH2:22]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:13])=[O:16])([CH3:41])[CH3:40]
Reactant: CC(C)(C)N
Reactant: CC(C(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C(=O)NC(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h

Procedure:
A stirred suspension of 3-oxopregn-4-ene-20-carboxylic acid (1.7 g, 5.0 mmole) in benzene (35 mL) was mixed with pyridine (0.56 mL, 6.25 mmole), cooled in an ice-water bath and treated with oxalyl chloride (0.56 mL, 6.45 mmole). The cooling bath was removed and the reaction mixture was stirred for 1.5 hours. The resulting mixture was then cooled in ice and treated slowly with tert-butylamine (2.9 mL, 29 mmole). After thirty minutes, the mixture was diluted with methylene chloride (100 mL), extracted with 5% hydrochloric acid, dried over magnesium sulfate, treated with charcoal, and filtered. The resulting filtrate was concentrated to give a yellow solid which was dissolved in methylene chloride and purified by flash chromatography (hexane-40% ethyl acetate). The product obtained in this way was subjected to flash chromatography again (hexane-30% ethyl acetate) and the resulting product was recrystallized from acetone to give N-(1,1-dimethylethyl)-3-oxopregn-4-ene-20-carboxamide. IR 3445, 3375, 1670 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Cl>[Fe].CO>[NH2:13][C:4]1[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1c(C(C)=O)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1c(N)cc(Br)cc1C(C)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Iron (15 g) was added to a mixture of the 1-(5-bromo-2-methoxy-3-nitrophenyl)-1-ethanone (16.2 g), concentrated hydrochloric acid (20 mL) and methanol (60 mL) at room temperature. After stirring the mixture at 60° C. for 1 hour, it was neutralized with saturated aqueous sodium hydrogencarbonate and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (12.8 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[CH2:13]([O:15]C(=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14].CCCCCCC.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[C:7]([CH2:8][CH2:14][CH2:13][OH:15])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(F)c(C=O)c1O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1ccc(F)c(CCCO)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 4.46 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde in 50 ml of dichloromethane there was added 10 g of (triphenyl phosphoranylidene)acetic acid ethyl ester while cooling on ice. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a silica gel column and elution was performed with heptane-ethyl acetate=3:1. The eluate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate, 1 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of THF, and then 2 g of lithium borohydride was added while cooling on ice and the mixture was stirred overnight at room temperature. After adding 1N hydrochloric acid to the reaction mixture while cooling on ice, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.78 g) as a solid.