Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([Mg]Br)[CH:13]=[CH2:14].[Cl-].[NH4+]>C(OCC)C>[C:1]1([CH2:7][O:8][CH2:9][CH:10]([OH:11])[CH2:14][CH:13]=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[Mg]Br
Reactant: O=CCOCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC(O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring 0° C. solution of 59.0 g of product from Example 1 in 375 ml of diethyl ether is added, dropwise, 432.24 ml of 1M allylmagnesium bromide in ether. The reaction is stirred at 0° C. for 1 hour, followed by overnight stirring at room temperature. The reaction is cooled to 0° C., hydrolyzed with saturated ammonium chloride, and the layers are separated. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100° C.) to give 61.5 g of the desired product as a colorless oil.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23]C4CCCCO4)[C:15]([C:16]#[N:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.Cl.CCOCC>CO>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][OH:23])[C:15]([C:16]#[N:17])=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: N#Cc1cnc(Oc2ccc3c(c2)COB3O)cc1OCCOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: N#Cc1cnc(Oc2ccc3c(c2)COB3O)cc1OCCO
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a suspension of 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-nicotinonitrile (1.8 g, 4.54 mmol) in methanol (15 mL) at 0° C. was added 1M HCl in ether (5.45 ml, 5.45 mmol) and left at the same temperature for 2 h. The solid that formed was collected by filtration and dissolved in minimum volume of 10% MeOH/CHCl3 and passed through a short column. The solvent was evaporated to yield the title compound (D119) (0.28 g, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 8.45 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.15-7.09 (m, 1H), 7.01 (s, 1H), 5.04 (t, J=5.3 Hz, 1H), 4.99 (s, 2H), 4.30 (t, J=4.5 Hz, 2H), 3.79-3.76 (m, 2H); MS (ES) m/z: 313 (M+1)+; HPLC purity 99.27% (Maxplot), 99.66% (220 nm). Elemental analysis for C15H13BN2O5: Calculated C, 57.73; H, 4.20; N, 8.98. found C, 57.53; H, 4.31; N, 8.95.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])(=[O:6])=[O:5].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([CH2:17][N:9]([CH2:8][CH2:7][S:4]([CH3:3])(=[O:5])=[O:6])[C:10](=[O:15])[C:11]([F:12])([F:14])[F:13])=[O:19])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)CCNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCS(C)(=O)=O)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.190 g, 4.75 mmol) was added to a solution of N-(2-methylsulphonylethyl)trifluoroacetamide (0.986 g, 4.50 mmol) in dry DMF (10 ml) and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Ethyl bromoacetate (0.55 ml, 0.828 g, 4.96 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water, and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), and concentrated in vacuo to give the title compound as a white solid (1.239 g, 4.03 mmol, 90%); δH CDCl3 4.17 (4H,m), 3.91 (2H,t), 3.46 (2H,t), 2.98 (3H,s), 1.30 (3H,t).
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C.Cl>O>[C:12]1([C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: OB(O)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
In 400 ml of water, 21.7 g of 5-bromosalicylic acid, 13.41 g of phenylboric acid and 15.28 g of potassium carbonate were dissolved. The solution was stirred at room temperature for 40 minutes. After the completion of the reaction was confirmed with TLC, the reaction liquid was poured into a mixed medium of diluted hydrochloric acidethyl acetate. The mixture was extracted, and the organic phase was collected and washed with saturated sodium chloride aqueous solution. After dried with magnesium sulfate, the liquid was concentrated to form a crude product. The product was recrystallized from acetonitrile to obtain 18.58 g of 5-phenylsalicylic acid in the form of colorless crystallites. The yield was 87%. The product was confirmed with NMR and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[CH3:13].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:9](=[O:10])[N:19]([C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1)[C:6]2=[O:8]
Reactant: Cc1cc2c(cc1C)C(=O)OC2=O
Reactant: Nc1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)C(=O)N(c1ccc(F)cc1)C2=O
Yield: 77.4 %

Procedure:
4,5-dimethylphthalic anhydride (1.7 g, 9.6 mmol) and 4-fluoroaniline (1.1 g, 9.6 mmol) were stirred with heating in dimethylformamide at 150° C. for 1 hr. After cooling, water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried. The resulting crystals were purified by silica gel chromatography (chloroform) to give 2.0 g of 5,6-dimethyl-2-(4-fluorophenyl)isoindolin-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH2:23][CH2:24][CH3:25]>CN1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH2:23][CH2:24][CH3:25]
Reactant: CCCI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCCn1c2c(c(=O)n1-c1ccccc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 25.5 %

Procedure:
A solution of (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 39; 151 mg, 0.5 mmol) and iodopropane (0.25 mL, 2.54 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube overnight. The reaction mixture was purified by preparative HPLC to give a brown gum which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1-propyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (44 mg, 26%) as a light brown gum. ES(+)-MS (M+H) 345.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7](=[N:16][OH:17])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Cl[CH2:27][C:28](=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CN(C)C=O>[CH2:33]([O:32][C:30]([CH2:29][C:28](=[O:35])[CH2:27][O:17][N:16]=[C:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:31])[CH3:34]
Reactant: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
2.57 g (0.01 mol) of the 4,4'-dimethoxybenzophenone oxime as obtained in (1) was dissolved in 5 ml of dimethylformamide and 1.2 g of potassium tert-butoxide was added thereto under ice cooling. The resulting mixture was stirred for ten minutes. Then 1.8 g of ethyl 4-chloroacetoacetate was added thereto and the obtained mixture was stirred at room temperature. After two hours, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethanol. The crude product thus obtained was purified by silica gel chromatography to give 3.1 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=1)[OH:11])[CH3:18]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
To 5-bromosalicylic acid (25 g, 115 mmol) in ethyl alcohol (300 mL) was added sulfuric acid (98%, 2 mL). The mixture was refluxed in a Dean-Stark apparatus for 2 days. The reaction mixture was cooled to room temperature. Most of the ethyl alcohol was removed by distillation. The residue was diluted with ethyl acetate, washed with water, aq. Na2CO3 and brine. The organic layer was dried (Na2SO4) and the solvent was removed to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].[H-].[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of the compound obtained in Example 27 (2) (1.2 g) and N,N-dimethylformamide (23 ml), 60% sodium hydride (204 mg) was added at 0° C. and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added 4-fluorobenzyl bromide (0.65 ml) at 0° C. and the mixture was stirred at 15 to 30° C. for 2 hours. 2N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane) to obtain 1 g of the desired product in a white amorphous form.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl>ClCCl>[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a dichloromethane solution (1000 ml) of (2R)-2-(benzyloxy)propionic acid (51.7 g) and tert-butyl 4-aminopiperidine-1-carboxylate (63.2 g) were added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60.5 g) and 1-hydroxybenzotriazole monohydrate (42.7 g), followed by stirring overnight. The reaction solution was poured into a 0.5 N aqueous hydrochloric acid solution, and extracted with dichloromethane. The organic layer was washed sequentially with water, a saturated aqueous sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-{[(2R)-2-(benzyloxy)propanoyl]amino}piperidine-1-carboxylate (100 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:48][C:49]1[C:50]([F:57])=[C:51](O)[C:52]([F:55])=[CH:53][CH:54]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][C:51]4[C:52]([F:55])=[CH:53][CH:54]=[C:49]([Cl:48])[C:50]=4[F:57])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1c(F)ccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCOc4c(F)ccc(Cl)c4F)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C

Procedure:
This compound is prepared from compound E4 and 3-chloro-2,6-difluorophenol, according to the above-described procedure A.
Reaction SMILES: O1[CH:24]2[C:25](=[O:26])[C@:2]31[O:29][C@:3]13[C@:22]([CH3:27])([CH2:23]2)[C@@H:21]2[C@H:6]([C@H:7]3[C@:18]([CH3:28])([CH2:19][CH2:20]2)[C@@H:10]([CH:11]([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:9][CH2:8]3)[CH:5]=[CH:4]1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH2:44].OO>O1CCCC1>[CH3:16][O:15][CH:12]([O:13][CH3:14])[CH:11]([CH3:17])[C@@H:10]1[C@:18]2([CH3:28])[C@H:7]([C@H:6]3[C@H:21]([CH2:20][CH2:19]2)[C@:22]2([CH3:27])[C@:3]([OH:29])([CH2:2][C@@H:25]([OH:26])[CH2:24][C@@H:23]2[OH:44])[CH:4]=[CH:5]3)[CH2:8][CH2:9]1
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]45O[C@]46OC(C[C@]5(C)[C@H]3CC[C@]12C)C6=O
Reactant: O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of tetrahydrofuran was dissolved 8.5 g of the 1α,2α;4α,5α-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3-one obtained in Example 76, followed by dropwise addition of 100 ml of a 1.0M solution of lithium tri-sec-butylborohydride in tetrahydrofuran under ice-cooling. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. The excess reducing agent was decomposed with water and the residual alkylborane was decomposed with alkaline hydrogen peroxide, followed by extraction with ethyl acetate. The extracts were pooled, washed with aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentration under reduced pressure. Recrystallization of the concentrate from ethyl acetate gave 2.90 g of 21,21-dimethoxy-20-methylpregn-6-ene-1α,3β,5α-triol showing the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:43]=[C:39]1[CH2:40][CH2:41][CH2:42][N:38]1[C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:10]2)=[O:29])=[CH:33][CH:34]=1
Reactant: NCc1ccc(N2CCCC2=O)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCc2ccc(N3CCCC3=O)cc2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl phenyl pyrrolidin-2-one (42.94 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 4-(2-oxo-pyrrolidin-1-yl)-benzylamide (48.9 mg, 40.5%) as an off-white powder. HRMS (ES+) m/z Calcd for C34H36Cl2N4O2S+H [(M+H)+]: 603.2288. found: 603.2289.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=O)=[C:10]2[N:9]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].N1CCCCC1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])=[C:10]2[N:9]=1
Reactant: O=Cc1cnn2ccc(-c3ccccc3F)nc12
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccccc4F)nc23)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (33 mg, 0.137 mmol) in 3 mL ETOH was added thiazolidine-2,4-dione (16 mg, 0.137 mmol) and piperidine (14 μL). The mixture was stirred at R.T. overnight. The solid formed was isolated by filtration and washed with EtOH to give 5-((5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>N1C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2nc(Oc3ccccc3)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
A solution of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) in pyridine (10 ml) was cooled to 0° C. and treated dropwise with phenyl chloroformate (3.3 ml, 26 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 h, after which time the pyridine was removed in vacuo. The residue was washed with water (20 ml) and dried in vacuo. Recrystallisation from toluene afforded the desired product as a pale brown solid (692 mg, 41%); δH (400 MHz, DMSO-D6) 2.40 (3H, s, CH3), 7.33-7.45 (3H, m, Ph), 7.48-7.55 (3H, m, Ph), 7.63 (1H, d, J 8, Ph), 7.89 (1H, s, Ph-H5); m/z (ES+) 254 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([NH:9][CH2:8][C@H:7]([NH:30][S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[C:6]([OH:40])=[O:5])=[O:29])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCOc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
8-5 (497 mg, 1.04 mmol) in 5 mL CH2Cl2 was treated with 5 mL TFA at 0° for 30 min then RT for 10 min. Concentration provided 9-1 as a yellow oil.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([N+:36]([O-])=O)[CH:24]=2)([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:39]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:36][C:25]1[CH:24]=[C:23]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]([NH2:39])[CH:10]=2)([C:19]([F:20])([F:21])[F:22])[C:15]([F:17])([F:18])[F:16])[CH:28]=[CH:27][C:26]=1[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(Nc3ccccc3)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(c2ccc(Nc3ccccc3)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Yield: 49 %

Procedure:
34.6 g (0.06 mol) of 2,2-bis-(4-anilino-3-nitrophenyl)-hexafluoropropane in 220 ml of ethanol are reduced with hydrogen under the catalytic action of 2 g of Pd-on-C (5% by weight in active charcoal) in a 500 ml chromium nickel steel autoclave. The crude product (30.7 g - pure according to H-NMR) is filtered off and recrystallized twice to give 15.1 g of analytically pure 2,2-bis-(3-amino-4-anilinophenyl) -hexafluoropropane (49% yield). The melting point is 177-178° C., and differs from the melting point given in the literature (120° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[N:18]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[C:20]([C:21]#[N:22])=[C:16]3[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:40]>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:17]3[N:18]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][CH:28]=4)[C:20]([C:21]([NH2:22])=[O:40])=[C:16]3[NH:15][CH2:14]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC21CCN(Cc2ccccc2)CC1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC21CCN(Cc2ccccc2)CC1

Procedure:
The desired product was prepared from 1′-benzyl-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carbonitrile according to the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J=8.4 Hz, 2H), 7.45-7.39 (m, 3H), 7.37-7.31 (m, 4H), 7.16 (t, J=7.6 Hz, 1H), 7.12-6.94 (m, 4H), 6.43 (s, 1H), 3.78 (s, 2H), 3.55 (br s, 2H), 2.89-2.82 (m, 2H), 2.15-2.11 (m, 2H), 1.84-1.72 (m, 2H). MS (ESI, m/e) [M+1]+ 479.9.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][CH2:9][C:10]#[N:11])=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.[NH4+].[Cl-]>N>[CH3:13][O:12][C:6]1[C:7]2[CH2:8][CH:9]([C:10]#[N:11])[C:2]=2[CH:3]=[CH:4][C:5]=1[O:14][CH3:15]
Reactant: COc1ccc(Br)c(CCC#N)c1OC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc2c(c1OC)CC2C#N
Temperature: -50 °C
Yield: 96.5 %

Procedure:
A mixture of liquid NH3 (400 mL) and catalytic Fe(NO3)3 was stirred under N2 at -50° C. A small portion of Na metal (from a total amount of 20 g., 0.87 mole) was added. Air was bubbled through the reaction mixture briefly until a black precipitate appeared. The remaining Na was added portionwise. 3-(6-bromo-2,3-dimethoxyphenyl)-propionitrile (31.1 g, 0.115 mole) was added over 70 minutes as the reaction mixture was stirred at slow reflux. When the addition was complete, the reaction mixture was stirred at reflux for 1/2 hr, then was cooled to -55° C. as NH4Cl (35.2 g, 0.66 mole) was added slowly. NH3 was allowed to evaporate overnight. Water was added cautiously with stirring. The solid was filtered, washed with water, dried (in-vacuo) to yield 21.0 g gray powder, (97%); M+ 189.