Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li]N1C(C)(C)CCCC1(C)C.[Li]CCCC.CC1CCCN(C)C1(C)C.[C:41](=[O:43])=[O:42]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[C:41]([OH:43])=[O:42]
Reactant: O=C=O
Reactant: Fc1cc(F)cc(-c2ccccc2)c1
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cc(-c2ccccc2)cc1F
Yield: 77 %

Procedure:
Dissolve crude 3,5-difluorbiphenyl (1.3 g, 6.83 mmol) in THF (14 mL) and cool to. −78° C. Prepare LiTMP from the addition of BuLi (1.6 M soln in hexanes, 5.33 mL) to tetramethyl piperidine (1.4 mL, 1.25 equiv) at −78° C. in THF (14 mL). Cannulate the cooled LiTMP into the cooled 3,5-difluorobiphenyl and stir the reaction at −78° C. for 1 h. Bubble carbon dioxide gas through the solution for 5 minutes, warm the reaction to rt, pour into 50 mL of 1M NaOB, and extract with 50 mL EtOAc. Discard the organic layer was discarded. Acidify the remaining aqueous layer with conc. HCl and extract twice with EtOAc. Dry the organics over MgSO4, filtered, and evaporate to give 1.22 g of the title compound as a white solid (77%). MS (m/e): 233.1 (M−).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[CH:7]=1)=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1C=CC=CC=1>[CH2:1]([NH:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[CH:7]=1)=[S:29])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCNC(=O)C1=CC(C)(C)Oc2ccc(C#N)cc21
Solvent: c1ccccc1
Product: CCNC(=S)C1=CC(C)(C)Oc2ccc(C#N)cc21
Yield: 80.7 %

Procedure:
A mixture of 0.14 g of N-ethyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbamide, 3.45 g of Lawesson's reagent, and 10 ml of benzene was refluxed for 1 hour. Any insoluble matter was collected by filtration with suction and washed with methylene chloride. The mother liquor and the washing were combined, and the solvent was removed therefrom by distillation. The residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.12 g of N-ethyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C@H:9]1[CH2:37][C@@:36]2([CH3:38])[C@@H:20]([CH2:21][C@@H:22]([CH3:39])[C@@H:23]2[C:24](=[O:35])[CH:25]([O:27][C:28](=[O:34])[C@@H:29]([NH2:33])[CH:30]([CH3:32])[CH3:31])[OH:26])[C@H:19]2[C@H:10]1[C@:11]1([CH3:42])[C:16]([C@@H:17]([F:40])[CH2:18]2)=[CH:15][C:14](=[O:41])[CH:13]=[CH:12]1.[NH:43]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C@H:44]([C:46]([NH:48][C@H:49]([C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@H:54]1[C:55](O)=[O:56])=[O:52])[CH3:50])=[O:47])[CH3:45].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:40][C@@H:17]1[C:16]2[C@:11]([CH3:42])([CH:12]=[CH:13][C:14](=[O:41])[CH:15]=2)[C@@H:10]2[C@H:19]([C@H:20]3[C@:36]([CH3:38])([CH2:37][C@@H:9]2[OH:8])[C@@H:23]([C:24](=[O:35])[CH:25]([O:27][C:28](=[O:34])[C@H:29]([CH:30]([CH3:32])[CH3:31])[NH:33][C:55](=[O:56])[C@@H:54]2[CH2:58][CH2:59][CH2:60][N:53]2[C:51](=[O:52])[C@H:49]([CH3:50])[NH:48][C:46](=[O:47])[C@H:44]([CH3:45])[NH:43][C:61]([O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[O:62])[OH:26])[C@H:22]([CH3:39])[CH2:21]3)[CH2:18]1
Reactant: CC(C)[C@H](N)C(=O)OC(O)C(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(O)C(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
884 mg (1.50 mmol) of H-Val-O-FC x TFA (Example 31), 500 mg (1.40 mmol) of Boc-Ala-Ala-Pro-OH and 168 mg (1.40 mmol) of N-hydroxybenzotriazole are dissolved in this sequence in 50 ml of dichloromethane and 330 μl (3.00 mmol) of N-methylmorpholine is added. Then, a solution of 289 mg (1.40 mmol) of dicyclohexylcarbodiimide in 2 ml of dichloromethane is added and stirred for 2 hours at room temperature. Then, it is suctioned off from precipitated urea, the filtrate is concentrated by evaporation and filtered again. Chromatography of this amount of raw material (300 g of silica gel, hexane/acetone 1:1) yields 861 mg (76%) of N-(N-(N-(N-((1,1-dimethyl) ethoxycarbonyl) -L-alanyl) -L-alanyl)-L-prolyl)-L-valine [6α-fluoro-11β,21-dihydroxy-16α-methyl-3,20-dioxo-pregna-1,4-dien-21-yl] ester. 737 mg of pure product is obtained [one or more words missing] recrystallization from dichloromethane/diisopropyl ether.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][CH:14]=2)[C:9]([CH:26]=O)=[N:8]1.[C:28]1([NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH2:34].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:34]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:35]=[C:26]1[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH:11]=2)[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccc(C(F)(F)F)c3)cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)phenyl)-1H-indazole-3-carbaldehyde (15 mg, 0.040 mmol) and o-phenylene diamine (5 mg, 0.046 mmol) were dissolved in dry THF (5 mL) and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (25 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR (400 MHz, CD3OD): δ 9.91 (s, 1H), 8.81 (s, 1H), 7.89-7.82 (m, 2H), 7.66 (m, 2H), 7.55-7.44 (m, 3H), 7.24 (m, 2H), 5.77 (dd, 1H, J=2.4 and 9.2 Hz), 4.02 (m, 1H), 3.75 (m, 1H), 2.59 (m, 1H), 2.12 (m, 2H), 1.75 (m, 3H); ESI-MS [M+H]+: 463.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[C@@H:9]3[CH2:13][CH2:14][N:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1.[Li+:17].[CH3:18][CH:19]([N-:21][CH:22]([CH3:24])[CH3:23])[CH3:20].C(NC(C)C)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N+:49]([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])#[C-:50].C(=O)=O.[Cl-].[NH4+]>C1COCC1.CN1C(=O)N(C)CCC1.C1COCC1.C([Li])CCC.CCCCCC>[Li+:17].[CH3:18][CH:19]([N-:21][CH:22]([CH3:24])[CH3:23])[CH3:20].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:50]=[N:49][C:51]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[C:10]3[C@@H:9]3[CH2:13][CH2:14][N:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C1Nc2ccc(Cl)cc2C(=O)N2CC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(Cl)ccc1-2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 54 %

Procedure:
23.6 g (0.1 mol) of (S)-6-chloro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione in 300 ml of THF/DMPU 5:1 were added dropwise under argon at about -75° to a LDA solution (prepared in the usual manner from 16 ml (0.11 mol) of diisopropylamine in 200 ml of THF and 69 ml of 1.6M n-butyllithium solution in hexane). The mixture was stirred for a further 40 min. 23 ml (0.11 mol) of diphenyl chlorophosphate were added dropwise thereto at about -75° and the mixture was stirred at -75° for 35 min. In the meanwhile and separately, a further LDA solution was prepared as described above (100 ml of THF). Thereto there was now added dropwise at about -75° a solution of 12.0 ml (0.11 mol) of ethyl isocyano- acetate in 20 ml of THF/DMPU 1:1. The deprotonized ethyl isocyanoacetate was added dropwise at about -70° via a dropping funnel cooled with dry ice within 30 min. to the initially described reaction mixture. The mixture was stirred in an acetone/dry-ice bath for 2 hrs, 100 ml of 20% ammonium chloride solution were added at <-60° and the mixture was poured into 800 ml of ice-water. The mixture was extracted three times with 200 ml of methylene chloride, dried with sodium sulfate and evaporated. The brown oil was dissolved in 300 ml of ethyl acetate, whereupon 300 ml of n-hexane were added slowly. The crystals were filtered off. Further product was obtained by chromatography of the mother liquor on 300 g of silica gel (methylene chloride/acetone 9:1). After drying in a vacuum there were obtained 17.8 g (54%) of ethyl (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of m.p. 190°-194° (ethyl acetate).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH2:15])[C:7]=2[CH:16]=1)#[N:2].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>C(O)C.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:22]3[CH:23]=[C:18]([Cl:17])[N:19]=[CH:20][N:21]=3)[C:7]=2[CH:16]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Nc2cc(Cl)ncn2)[C@@H]1O

Procedure:
A solution of trans-6-cyano-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (prepared as described in U.S. Pat. No. 4,446,113) (2.0 g) and 4,6-dichloropyrimidine (1.5 g) in ethanol (25 mL) and triethylamine (1.3 mL) was heated under reflux for 72 h. The solution was allowed to cool and the precipitate filtered off, and dissolved in ethyl acetate. The ethyl acetate solution was washed with water, 0.5N hydrochloric acid, sodium bicarbonate solution, brine, and then dried (Na2SO4). Removal of drying agent and solvent gave the title compound as a solid (1.08 g). A sample recrystallised from acetonitrile had m.pt. 204°-8° C.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:12]2[CH2:17][CH2:16][CH:15]([O:18][N:19]3[C:27](=[O:28])C4C(=CC=CC=4)C3=O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=C=O)=[CH:40][CH:39]=1>C(Cl)Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH:19][C:27]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)=[O:28])[CH2:14][CH2:13]2)=[CH:31][CH:32]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: O=C(NOC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 131.7 %

Procedure:
Hydrazine monohydrate (0.059 ml, 1.2 mmol) was added to a solution of 2-(1-(bis(4-fluorophenyl)methyl)piperidin-4-yloxy)isoindoline-1,3-dione (193 mg, 0.406 mmol) in CH2Cl2 (5 ml) and stirred at room temperature for 15 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 ml), 4-fluorophenyl isocyanate (0.023 ml, 0.20 mmol) was added and the whole was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo, the residue was purified by column chromatography (ethyl acetate/hexane: 25/75 to 45/55) and the resulting solid was recrystallized from ethyl acetate/hexane to give 1-(1-(bis(4-fluorophenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)urea (120 mg, 65%) as a white solid: LCMS: 456 [M+1]+. 1H NMR (DMSO-d6) δ: 1.68 (m, 2H), 1.90-2.02 (m, 4H), 2.62 (m, 2H), 3.70 (m, 1H), 4.40 (s, 1H), 7.10 (m, 6H), 7.43 (m, 4H), 7.55 (m, 2H), 8.61 (s, 1H), 9.38 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([NH2:16])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[CH3:19][N:20]=[C:21]=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([NH:16][C:21]([NH:20][CH3:19])=[S:22])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: Nc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Solvent: c1ccncc1
Product: CNC(=S)Nc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 100 °C
Yield: 58 %

Procedure:
A solution of obtained amine from Example 263 (150 mg, 0.542 mmol) in 5 mL of pyridine was treated with methyl isothiocyanate (198 mg, 2.71 mmol). The solution heated to 100° C. under a nitrogen atmosphere for 5 days. All volatiles were removed under reduced pressure. The resulting product was purified by flash column chromatography on silica gel eluting with chloroform/NH4OH, affording 110 mg (58.1%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH:4]([OH:20])[CH2:3]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32](O)=[O:33])=[CH:23]1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.ON1C2C=CC=CC=2N=N1>[CH3:1][C:2]1([CH3:21])[CH:10]2[CH:6]([CH2:7][N:8]([C:32](=[O:33])[CH2:31][C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][CH:23]=3)[CH2:9]2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])([OH:11])[CH:4]([OH:20])[CH2:3]1
Reactant: COc1ccccc1C1(O)C(O)CC(C)(C)C2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C1(O)C(O)CC(C)(C)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.9 %

Procedure:
To a solution of 0.44 g of (3aRS,4RS,5RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol and 0.29 g of 3-indoleacetic acid in 40 cm3 of dichloromethane, cooled to 0° C., are added 5 mg of 1-hydroxybenzotriazole, 0.35 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.42 cm3 of diisopropylethylamine. The mixture is stirred for 15 hours at room temperature, 100 cm3 of dichloromethane are added and the organic phase is washed with 50 cm3 of aqueous sodium bicarbonate solution and with 60 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The cream-coloured foam obtained is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 1 cm, height 30 cm), eluting under a pressure of 0.5 bar nitrogen with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 30 cm3 fractions. Fractions 5 to 7 are combined and then concentrated to dryness under reduced pressure (2.7 kPa); the solid obtained is recrystallized in 5 cm3 of isopropyl ether. 0.48 g of (3aRS,4RS,5RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(3-indolyl)acetyl]-4,5-perhydroisoindolediol is obtained, melting at 160-165° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)OC)#[N:2].[N+]([O-])(O)=O.[O:21]([CH2:25][CH2:26][NH2:27])[N+:22]([O-:24])=[O:23].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:27][CH2:26][CH2:25][O:21][N+:22]([O-:24])=[O:23])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1cnc2ccccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCO[N+](=O)[O-])c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
Methyl N-cyano-3-quinolinecarboximidate (0.32 g, 1.5 mmol) was dissolved in methanol (3 ml), 2-nitroxyethylamine nitrate (0.42 g, 2.5 mmol) and sodium methoxide (0.12 g, 2.2 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with dichloromethane-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from dichloromethane-diethyl ether to give the title compound (0.23 g, 0.80 mmol, yield: 54%) as colorless crystals.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[OH:6])([O-])=O>CO.O=[Pt]=O>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[OH:6]
Reactant: COc1cccc(C(O)C[N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CO
Product: COc1cccc(C(O)CN)c1
Reaction time: 8 h
Yield: 29 %

Procedure:
A suspension of 2-nitro-1-(3-methoxyphenyl)ethanol (688 mg, 3.49 mmol), PtO2 (160 mg) in MeOH (10 mL) was pressurized to 40 psi H2 and shaken in a Parr shaker overnight. The reaction was depressurized, filtered through Celite, concentrated, purified by flash chromatography (0-100% EtOAc:hexane) to afford 169 mg of the product as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.24 (t, J=7.96 Hz, 1H), 6.85-6.93 (m, 2H), 6.80 (m, 1H), 4.60 (dd, J=7.83, 4.04 Hz, 1H), 3.79 (s, 3H), 2.96 (dd, J=12.76, 3.92 Hz, 1H), 2.79 (dd, J=12.76, 7.71 Hz, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:10](=[O:12])[C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[C:18]=3[O:20][CH3:21])[CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cc2cc(OC)c(OC)c(OC)c2)C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C2Cc3cc(OC)c(OC)c(OC)c3C2=O)cc1
Temperature: 0 °C

Procedure:
A solution of the acid 33 (0.5 g, 1.4 mmol) in phosphorous oxychloride (5 mL, 53.4 mmol) was heated at reflux for 3 min. The dark red solution was poured onto crushed ice (about 30 g) and extracted with ether (50, 20, and 20 mL). The combined ether layer was dried over anhydrous sodium sulfate. Evaporation of the filtrate gave a gray solid. Recrystallization of this gray solid from ethyl acetate and hexane afforded pale gray crystals 0.32 g (69.6%): mp 104°-106° C.; IR (KBr) 3010, 2960, 1697, 1595, 1512, 1323, 1251, 1139 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ7.11 (d, 2H, J=8 Hz), 6.85 (d, 2H, J=8 Hz), 6.71 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H), 3.78 (m, 1H), 3.54 (m, 1 H), 3.10 (m, 1H); EIMS m/e 328 (M+, 98). Anal. (C19H20O5), C, H.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:21]=[C:20]3[C:14]([CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]3)=[N:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl>O1CCOCC1.CO>[N:13]1[N:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=2)[CH:21]=[C:20]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][C:14]=12
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(NS(C)(=O)=O)cc3)nc2CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 2-{4-[(methylsulfonyl)amino]phenyl}-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 39) (16 mg, 0.039 mmol) in dioxan (1 ml) was added 4M hydrochloric acid in dioxan (2 ml). The resulting mixture was stirred at room temperature, under argon, overnight. The reaction mixture was diluted with methanol and then purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (D40). MS (ES+) m/e 307 [M+H]+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]3)([O:3][CH3:4])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1C([N+]([O-])=O)=CC=C(O)C=1>O1CCOCC1>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH:17]=[CH:18]1)[N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(=O)OC(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(=O)OC(C)(C)C)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C

Procedure:
A solution of 17β-carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one (2.00 g, 4.63 mmol), prepared in example 1, part E, in dioxane (50 mL) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.37 g, 6.02 mmol) and p-nitrophenol (10 mg). The reaction is heated to reflux for 2 hrs, poured into ice water (150 mL), extracted with ethyl acetate (3×100 mL), extracts washed with saturated aqueous NaHSO3, 2N NaOH, saturated aqueous NaCl, dried over MgSO4, concentrated and chromatographed on silica gel (40% ethyl acetate/hexanes) to give crude 17β-carbomethoxy-6-t-butoxycarbonyi-6-azaandrost-1,4-dien-3-one as a tan solid of sufficient purity to carry on to the following steps; yield: 1.53 g (76%).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@H:3]([C:7]([NH:9][C:10]1([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:12][CH2:11]1)=[O:8])[NH:2]2.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:2]2[C@@H:3]([C:7]([NH:9][C:10]3([C:13]4[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=4)[CH2:11][CH2:12]3)=[O:8])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@@H]4C[C@@H]4N3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@@H]4C[C@@H]4N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D148) (100.8 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-((1S,3R,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (diastereoisomer trans) (D105) (71.9 mg) and 4-(trifluoromethyl)-benzylbromide (0.047 ml). (Na2CO3: 3 eq; Reaction time: 18 hrs; 68° C.)
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH:17](O)[CH3:18])[C:12]=1[CH3:20]>ClCCl>[Cl:10][C:11]1[C:12]([CH3:20])=[C:13]([CH:17]([F:7])[CH3:18])[N:14]=[CH:15][N:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1c(Cl)ncnc1C(C)O
Solvent: ClCCl
Product: Cc1c(Cl)ncnc1C(C)F
Temperature: -78 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
DAST (0.436 mL, 3.30 mmol) was added to dichloromethane (DCM) (11 mL), cooled to −78° C. and treated dropwise with a solution of 1-(6-chloro-5-methyl-4-pyrimidinyl)ethanol (Intermediate 44, 380 mg, 2.201 mmol) in DCM (4 mL) under argon. The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched by adding water (7 ml) and extracted with DCM (×2). The DCM layers were separated, combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (153 mg);