Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22]>O1CCOCC1>[C:21](=[O:22])([O:23][CH3:24])[O:12][C:6]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)ccc1O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Oc1ccc(F)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 2-tert-butyl-4-fluorophenol (2.63 g, 15.7 mmol) and NEt3 (3.13 mL, 22.5 mmol) in dioxane (45 mL) was added methyl chloroformate (1.27 mL, 16.5 mmol). The mixture was stirred at room temperature for 1 h. The precipitate was removed via filtration. The filtrate was then diluted with water and extracted with ether. The ether extract was washed with water and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography to give 2-tert-butyl-4-fluorophenyl methyl carbonate (2.08 g, 59%). 1H NMR (400 MHz, DMSO-d6) δ 7.24 (dd, J=8.8, 5.4 Hz, 1H), 7.17-7.10 (m, 2H), 3.86 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14](=O)[NH:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)=[N:11]2.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>N1C=CC=CC=1>[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[N:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)=[N:11]2
Reactant: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)nc(-n3cncn3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.35 g (15.35 mmol) of phosphoryl chloride are added dropwise under argon to a solution of 1.46 g (5.12 mmol) of 5,7-dimethyl-2-(3-nitrophenyl)imidazo-[5,1-f][1,2,4]triazin-4-(3H)one from example 9A in 50 ml of dry pyridine at 0° C. and the mixture is stirred for 30 min at RT. Subsequently, 3.18 g (46.06 mmol) of 1,2,4-triazole are added, and the mixture is stirred for 3 h at 20° C. The reaction mixture is concentrated, the residue is treated with aqueous sodium hydrogencarbonate solution and the mixture is extracted with dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (eluent: dichloromethane/methanol 100:1).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[C:9]3[CH:17]=[N:18][C:19]([N:21]([CH3:33])[C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:8]2=3)[CH2:6][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.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1>CN(C)C=O>[CH:1]1([N:7]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[C:9]3[CH:17]=[N:18][C:19]([N:21]([CH3:33])[C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:67][CH:68]5[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1N(C)c1ncc2c(n1)N(C1CCCCC1)CC(C)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N(C)c1ncc2c(n1)N(C1CCCCC1)CC(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of 0.058 g (0.00013 mole) of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-benzoic acid, 0.054 g (0.00014 mole) of 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 3 mL of N,N-dimethylformamide was added 0.030 mL (0.00019 mole) of ethyldiisopropylamine. The mixture was stirred at room temperature for 30 minutes and then 0.022 g (0.00019 mole) of 4-amino-1-methyl-piperidine was then added. The mixture was stirred at room temperature for 3 hours and was then partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed successively with water and brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75-25) to give 0.070 g of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-66) as white powder. HRMS (ES+) m/z Calcd for C30H43N7O3+H [(M+H)+]: 550.3500. Found: 550.3504.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2cccc(F)c2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(F)c3)CC2)cc1
Yield: 81.8 %

Procedure:
0.5 g (0.00239 mol) of 1-(3-fluoro-benzyl)-piperidin-4-ol and 0.67 ml (0.00478 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.632 ml (0.00478 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.64 g (82%) of 1-(3-fluoro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil. MS: me/e=328 (C20H23FNO2+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:31][CH:32]=[CH2:33])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH:20]([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC(C1C=C(C(C)C)C(S([N:60]=[N+:61]=[N-:62])(=O)=O)=C(C(C)C)C=1)C.CC(O)=O>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:31][CH:32]=[CH2:33])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][C@:20]([N:60]=[N+:61]=[N-:62])([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)CC2C
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)C[C@@]2(C)N=[N+]=[N-]
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a solution of the methyl diastereomers (18c) (3.90 g, 8.51 mmol) in 40 mL THF at −78° C., was added LiHMDS (IM in THF, 17.9 mL, 17.9 mmol). The red solution was stirred at −78° C. for 5 min, then a solution of trisyl azide (2.90 g, 9.36 mmol) in 8 mL THF was added. The reaction was stirred at −78° C. for 1.5 h, then was quenched with the addition of AcOH (2.19 mL, 38.3 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with 1N HCl, H2O and brine, dried (Na2SO4), and concentrated. The product was purified by flash chromatography (35 to 40% EtOAc/hexanes) to afford 2.764 g (65%) of azide 18d. MS (ESI) 500.4 (M+H+), 522.4 (M+Na+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=1>>[CH2:15]([N:22]([CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: NCc1ccccc1
Product: O=C(O)c1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from methyl-4-(chlorosulfonyl)benzoate (example 5-10c), benzyl amine and methyl 4-(bromomethyl)benzoate MS (M+H, 426.10); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 4.29 (s, 2H), 4.34 (s, 2H), 7.03 (m, 2H), 7.12 (m, 2H), 7.68 (d, J=8 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 8.06 (d, J=8.8 Hz, 2H), 13.03 (s, 2H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH:62]([NH2:65])[CH2:61][CH2:60]1>>[CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][CH:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and. 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.3 Hz, 3H) 1.60-1.75 (m, 11H) 1.84-2.09 (m, 5H) 2.19 (s, 3H) 2.80 (d, J=11.1 Hz, 2H) 3.26 (s, 3H) 3.60-3.83 (m, 3H) 3.94 (s, 3H) 4.78 (t, J=8.1 Hz, 1H) 7.35-7.60 (m, 2H) 7.80 (s, 1H) 8.08 (d, J=7.6 Hz, 1H) 8.16 (s, 1H) 8.32 (d, J=8.3 Hz, 1H). Melting point: 149-153° C. [M+H] calc'd for C29H40FN7O3, 554. found 554.
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][C:11]1[C:12]([C:16]([O:18]CC)=[O:17])=[N:13][NH:14][CH:15]=1.[Li+].[OH-].C(OCC)(=O)C>C1COCC1.O>[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][C:11]1[C:12]([C:16]([OH:18])=[O:17])=[N:13][NH:14][CH:15]=1
Reactant: CCOC(=O)c1n[nH]cc1CNc1ccccc1C(O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1n[nH]cc1CNc1ccccc1C(O)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 113.9 %

Procedure:
To a solution of product (1-A) (1.34 g, 3.8 mmol) in THF (30 mL) was added drop-wise a solution of LiOH (0.24 g, 10 mmol) in H2O (30 mL) at 0° C. The reaction mixture was stirred at 50° C. for about 2 h. After cooling, ethyl acetate (20 mL) and H2O (20 mL) were added to the solution. The aqueous layer was separated and acidified with citric acid (to pH=5) and extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated to give crude product (2-A) (1.4 g, 100%) as a light yellow solid. LC-MS (M+H)+=324.
Reaction SMILES: [CH:1]12[CH2:14][CH:9]([CH:10](O)[CH:11]1O)[CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]2=1.CCOC(C)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO.O>[CH2:21]([N:28]1[CH2:11][CH:1]2[CH2:14][CH:9]([CH2:8][C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=32)[CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC1C2Cc3cccnc3C(C2)C1O
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: c1ccc(CN2CC3Cc4cccnc4C(C3)C2)cc1
Reaction time: 0.25 h

Procedure:
3-Aza-tricyclo[7.2.1.02,7]dodeca-2(7),3,5-triene-10,11-diol (1.16 g, 6.07 mmol) was stirred in EtOH (40 mL) and was treated with a solution of NaIO4 (1.35 g, 6.07 mmol) in H2O (20 mL). A precipitate forms and the mixture becomes a yellow slurry. After 15 min, the reaction is deemed complete (TLC EtOAc Rf 0.62), diluted with water and extracted with dichloromethane (4×50 mL). The organic layer was washed with H2O (5×50 mL) then dried through a cotton plug and concentrated to an oil. This oil was stirred in DCE (50 mL), treated with benzyl amine (650 mg, 6.07 mmol) then sodium triacetoxyborohydride NaBH(OAc)3 (4.12 g, 19.4 mmol). The mixture was stirred 7 h, then was quenched by addition to saturated sodium carbonate (Na2CO3) solution and EtOAc (˜75 mL each). After stirring 20 min., the layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layer was washed with H2O (50 mL) and saturated aqueous NaCl solution (50 mL) then dried over Na2SO4. Filtration and concentration affords an oil, 1.2 g which was purified by chromatography on silica gel eluting with 50% EtOAc/hexanes to provide pure product as an oil, 802 mg (50%). (TLC EtOAc Rf 0.68); 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J=4.7, 0.6 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.13–7.07 (m, 4H), 6.85 (m, 2H), 3.35 (AB q, ΔAB=27.2, J=13.8 Hz, 2H), 3.08 (s, 1H), 3.02 (dd, J=17.3, 7.0 Hz, 1H), 2.92 (d, J=10.6 Hz, 1H), 2.81 (d, J=10.6 Hz, 1H), 2.74 (d, J=17.3 Hz, 1H) 3.34 (br d, J=10.6 Hz, 2H), 2.17 (br s, 1H), 1.90 (d, J=3.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 160.8, 145.6, 139.2, 134.7, 134.2, 128.1, 128.0, 126.6, 121.0, 62.3, 60.8, 58.9, 38.4, 34.2, 29.8, 28.4; APCl MS m/z 265.1 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=O.O.NN.[OH-].[K+]>C(O)COCCO>[NH:14]1[C:15]2[C:11](=[C:10]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: O=C(c1ccccc1O)c1cccc2[nH]ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Oc1ccccc1Cc1cccc2[nH]ccc12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 22.74 g of the product of Step D of Example 3, 49.4 ml of hydrazine monohydrate, 96 ml of diethylene glycol and 38.4 ml of 38% caustic potassium hydroxide was stirred for 30 minutes at 140° C. and after the mixture was heated to 210° C., the water and hydrazine hydrate were distilled off. Stirring was continued for one hour at 210° C. and the mixture was allowed to return to ambient temperature and poured into 300 ml of a saturated aqueous solution of sodium chloride. Extraction took place with ethyl acetate and the extracts were evaporated to dryness under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride) to obtain 20.55 g of the desired product melting at 139° C. which was used as is for the following step.
Reaction SMILES: [Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]([C:18]2[C:19]([Cl:25])=[N:20][CH:21]=[N:22][C:23]=2Cl)=O)[C:9]=1[F:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:27][NH2:28]>C1COCC1.O.CCOC(C)=O>[Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:18]3[C:23](=[N:22][CH:21]=[N:20][C:19]=3[Cl:25])[NH:28][N:27]=2)[C:9]=1[F:26])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: NN
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(=O)c2c(Cl)ncnc2Cl)c1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncnc(Cl)c23)c1F
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
[4-[tert-butyl(dimethyl)silyl]-3,5,6-trifluoro-2-pyridyl]-(4,6-dichloropyrimidin-5-yl)methanone (901 mg, 2.13 mmol) was dissolved in THF (18 mL) and cooled to −50° C. Hydrazine (1M in THF) (2.20 mL of 1 M, 2.20 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then allowed to warm to ambient temperature for 30 minutes. The reaction mixture was diluted with water and EtOAc. The organic layer was separated, washed with water (2×), brine, dried (MgSO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 80 g column, eluting with 0-3% MeOH/DCM) to give the sub title compound as an orange foam (498 mg, 58.4% Yield). H1 NMR (400 MHz, DMSO) δ 15.04 (1H, s), 8.92 (1H, s), 0.95 (9H, s) and 0.44 (6H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])[CH3:14]
Reactant: CCN
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: CCNC(=O)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and ethylamine; MS: 189.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:20][OH:21]>C(O)C.[Cl-].[Na+].O>[OH:21][N:20]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:14][CH2:15][CH2:16][O:17]2)=[O:8])=[CH:18][CH:19]=1)[NH2:2]
Reactant: NO
Reactant: N#Cc1ccc(C(=O)OCCCC2OCCO2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(C(=O)OCCCC2OCCO2)cc1
Temperature: 80 °C

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)propyl 4-cyanobenzoate (1.00 g, 4.38 mmol) in ethanol (5 mL), was added hydroxylamine (50% aqueous solution, 5 mL), and the mixture heated at 80° C. for 4 hours. The reaction was diluted with saturated brine and extracted with ethyl acetate (×3). The combined organic fractions were dried with magnesium sulphate, and the solvent evaporated at reduced pressure. The material was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([CH:10]1[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([CH:10]1[C:19]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:33][C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(CCCCCC)C(=O)C1CC(=O)c2ccccc2S1
Reactant: NNc1ccccc1
Product: CCCCCCN(CCCCCC)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Temperature: 170 °C
Reaction time: 0.08 h

Procedure:
N,N-Dihexyl-(4-oxo-thiochroman-2-yl)-carboxamide (1.00 g) and phenylhydrazine (0.26 ml) were stirred at 100° C. for 30 minutes, and the reaction mixture was dried under reduced pressure at 50° C. for 30 minutes. The residue, after addition of 1.44 g of anhydrous zinc chloride, was stirred at 170° C. for 5 minutes, and cooled to room temperature. To the reaction mixture was added ice water, followed by extracting with ethyl acetate. The extract was washed with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 0.79 g of N,N-dihexyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].Cl.[Br:13]Br>C(OCC)C.C(Cl)(Cl)Cl>[Br:13][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: BrBr
Reactant: CCc1ccc(C(C)=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCc1ccc(C(=O)CBr)cc1
Reaction time: 4 h

Procedure:
20 mmol of 1-(4-ethylphenyl)ethan-1-one, 1 ml conc. HCl were mixed in 20 ml diethyl ether at 0° C. under nitrogen. To this solution a solution of 20 mmol Br2 in 20 ml chloroform was added drop wise and left for four hours and then concentrated in vacuo to obtain 2-bromo-1-(4-ethylphenyl)ethan-1-one.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]([CH3:18])=[C:16]([CH2:19]Cl)[CH:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])[CH:28]=[CH:27]2.C([O-])([O-])=O.[Cs+].[Cs+].[C:45](#N)[CH3:46]>>[CH2:45]([O:35][C:34](=[O:36])[C:33]([N:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][CH2:19][C:16]3[CH:15]=[N:14][N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[C:17]=3[CH3:18])=[CH:32][CH:31]=2)[CH:27]=[CH:28]1)([CH3:38])[CH3:37])[CH3:46]
Reactant: CC#N
Reactant: Cc1c(CCl)cnn1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C(=O)O)n1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(C)(C)n1ccc2cc(OCc3cnn(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3C)ccc21
Temperature: 25 °C

Procedure:
To a solution of 1-(3,5-bis-trifluoromethyl-phenyl)-4-chloromethyl-5-methyl-1H-pyrazole (170 mg, 0.5 mmol) and (2-(5-hydroxy-indol-1-yl)-2-methyl-propionic acid (150 mg) in acetonitrile (3 mL) is added Cs2CO3 (325 mg, 1 mmol). The mixture is stirred at room temperature over night, quenched by water, extracted with ethyl acetate, dried over sodium sulfate. Concentration yields the crude product.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].C(OOC(C)(C)C)(C)(C)C>>[C:12]1([CH:10]([CH3:11])[O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCCCO
Reactant: CCc1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCCCCCOC(C)c1ccccc1
Temperature: 90 °C
Yield: 52 %

Procedure:
Into a pressure vessel 1-octanol (160 μL, 1 mmol, 1 eq) was added and diluted with ethylbenzene (1.225 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing ethylbenzene under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials. 1H NMR Yield: 52%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)ccc3Cl)c(=O)c12
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1cc(Cl)ccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
A mixture of (4S,7R)-2-(2,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 44; 12.55 g, 37.2 mmol) and iodomethane (12 mL, 193 mmol) in dimethylformamide (75 mL) was heated at 100° C. for 3 h and then cooled to room temperature. The solvent was evaporated, dichloromethane (300 mL) was added and the solution was washed with saturated aqueous sodium thiosulfate (100 mL), water (2×100 mL), and brine (100 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by flash column chromatography, eluting with 50-100% ethyl acetate/petroleum ether. Fractions homogeneous for the product were evaporated and ethyl acetate (100 mL) was added. The mixture was stirred at room temperature for 10 min and then hexane (300 mL) was added. The mixture was stirred at room temperature for 10 min and then cooled to 0° C. and filtered. The filter cake was washed with hexane and dried. The solid was dissolved in ethanol (100 mL) and treated with activated charcoal (0.8 g). The mixture was stirred at room temperature for 30 min, filtered through celite, and then evaporated. The residue was dried at 70° C. overnight to give (4S,7R)-2-(2,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (9.18 g, 70%) as a white solid. ES(+)-MS (M+H) 351.