Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:50]([CH2:52][NH2:53])[OH:51]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](=[O:16])[NH:53][CH2:52][CH2:50][OH:51])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NCCO)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
(S)-Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (500 mg, 2.2 mmol), HATU (833 mg, 2.2 mmol) and Di-isopropylethylamine (761 μL, 4.4 mmol) were stirred in dry DCM (10 ml) in an ice bath for 5 min, then at room temperature for 5 min. Ethanolamine (198 μL, 3.28 mmol) was added and the reaction stirred at room temperature for 3 hrs. The reaction was diluted with DCM (40 ml), washed with water (50 ml), the DCM layer separated and dried (MgSO4) and concentrated. The residue was columned on silica (20 g isolute). Eluting: MeOH/DCM 0-5% 5 CV, MeOH/DCM 5%-5% 10 CV, MeOH/DCM 5-10% 5 CV. TLC visualized with KMnO4. This yielded the product as a clear oil (327 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])=[CH:5][C:4]=1[F:18])#[N:2].[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[CH3:19])[CH2:10][CH:11]=[CH2:12])=[CH:5][C:4]=1[F:18])#[N:2]
Reactant: C=CCC(OS(C)(=O)=O)c1ccc(C#N)c(F)c1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCC(c1ccc(C#N)c(F)c1)n1ccnc1C
Temperature: 100 °C

Procedure:
To a solution of the methanesulfonate from Step I (17.3 mmol) in 20 mL of DMF was added 2-methylimidazole (4.25 g, 51.8 mmol) and potassium carbonate (7.15 g, 51.8 mmol). The reaction was heated to 100° C. for 3 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (3-6% MeOH/CH2Cl2) provided the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[C:14](=O)[CH3:15].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)(F)F)cc1Cl
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cc1Cl
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (390 mg, clear colorless oil) from 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1([NH:12][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Br:20])(=[O:29])=[O:28])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NS(=O)(=O)c2ccccc2Br)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
In a 50-mL flask, 1-amino-cyclohexanecarboxylic acid methylester hydrochloride (350 mg, 1.80 mmol) and methylenechloride (20 mL) were charged, and then triethylamine (0.836 mL, 5.99 mmol) was charged, followed by stirring for 30 minutes at room temperature. 2-bromo-benzenesulfonylchloride (383 mg, 1.49 mmol) was added thereto, followed by stirring for 12 hours at room temperature. Then, purified water (10 ml) was added thereto to bring the reaction to an end. The organic layer was separated, and washed with saturated ammonium chloride solution (20 ml). Then, the washed organic layer was separated, and added with magnesium sulfate so as to remove remaining moisture. Then, through filtering and vacuum distillation, the solvent was removed so as to obtain the residue. The mixture was purified with column chromatography (EA/n-Hex=1:5) so as to obtain 1-(2-bromo-benzenesulfonylamino)-cyclohexanecarboxylic acid methylester (285 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=C1C=CCC1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](c2ccc(Br)cc2)C1
Temperature: 35 °C
Yield: 88.7 %

Procedure:
Alternatively, a 3 L three-necked round-bottomed flask equipped with a temperature probe and a nitrogen bubbler was charged with 4-bromophenylboronic acid (100 g, 498 mmol) and hydroxy[(S)-BINAP]rhodium(I) dimer (6.20 g, 4.17 mmol) in dioxane (1667 mL) and water (167 mL) at room temperature. The resulting suspension was degassed with nitrogen and 2-cyclopenten-1-one (27.8 mL, 332 mmol) was added in one portion. The mixture was further degassed for 5 minutes and heated at 35° C. for about 16 hours. The reaction mixture was cooled to room temperature and concentrated. The brown residue was treated with EtOAc (500 mL) and filtered. The filtrate was washed with a saturated solution of NaHCO3 (500 mL) and brine (500 mL), dried over MgSO4, filtered, and concentrated to afford a dark brown solid. The crude reaction product was purified by silica gel chromatography (1:9 EtOAc:heptane as eluant). Fractions containing product were combined and concentrated to afford (S)-3-(4-bromo-phenyl)-cyclopentanone (70.4 g, 89%, 95% ee as determined by chiral HPLC) as an ivory solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[H][H]>C(O)C.[Pt]=O>[OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[CH:4]([CH3:13])[CH2:3]1
Reactant: [H][H]
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Agent: O=[Pt]
Solvent: CCO
Product: CC1=C2CCC(O)CC(C)C2CC1
Yield: 60.1 %

Procedure:
500 mg of platinum oxide were pre-hydrogenated in 300 ml of ethanol. After addition of 2.14 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene, the mixture was hydrogenated until hydrogen was no longer taken up. The reaction mixture was filtered, the filtrate evaporated and the crude product distilled under reduced pressure in a bulb-tube. There were obtained 1.3 g of pure 6-hydroxy-1,4-dimethyl-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.001 ca 85°; IR(film):νmax 3380, 1460, 1440, 1095, 1078, 1035/30, 985/75, 940 cm-1. The substance has a woody, flowery, fresh green odour.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:17]3([C:30]([O:32]CC)=[O:31])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:2]=1.[OH-].[K+]>C(O)C.O>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][C:17]([S:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:13][CH:12]=2)(=[O:15])=[O:16])([C:30]([OH:32])=[O:31])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3cccnc3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3cccnc3)cc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
1-(tert-butoxycarbonyl)-4-(4-(pyridin-3-yloxy)phenylsulfonyl)piperidine-4-carboxylic acid was prepared according to FIG. 3. A 250-mL round bottom flask was charged with 1.7 g ethyl ester (from step 1), 0.78 g (4 eq.) potassium hydroxide in 16 mL ethanol and 4 mL water. The reaction mixture was heated to 90° C. LCMS after 1 hour shows complete reaction. The mixture was partitioned between ethyl acetate and 10% aqueous KHSO4-Brine. The yellow organic phase was separated, dried, filtered and concentrated. The residue was vacuum dried overnight to produce 1.32 g off-white foam that was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].O.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: ClCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CCc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Into a 1,000 mλ reaction flask equipped with a thermometer, a stirrer, a condenser and a dropping funnel, 119.2 g (1.0 mol) of indoline, 105 g (1.25 mols) of sodium hydrogen carbonate and 200 g of water were charged, and the temperature was raised to a liquid temperature of 90° C. Then, while stirring at the same temperature, 132.9 g (1.05 mols) of benzyl chloride was dropwise added thereto over a period of about one hour from the dropping funnel, and then stirring was continued for eight hours at from 90 to 95° C. After completion of the reaction, 400 mλ of toluene was added, and the mixture was stirred from 60 to 80° C. for a while and then left to stand still for liquid separation. From the obtained organic layer, toluene was distilled off under reduced pressure to obtain 209 g of brown 1-benzylindoline (crude yield: 100%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH:4]([CH3:25])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[CH:11]=[CH:10]3)[CH2:7][CH2:6]1.[OH-:28].[Na+].OO>CO>[O:28]1[C@H:15]2[C:14](=[O:24])[CH:13]=[C:12]3[C@:17]([CH3:18])([C@@H:16]12)[C@@H:19]1[C@H:9]([C@H:8]2[C@:22]([CH3:23])([CH2:21][CH2:20]1)[C@@H:5]([CH:4]([CH3:25])[CH:3]([O:2][CH3:1])[O:26][CH3:27])[CH2:6][CH2:7]2)[CH:10]=[CH:11]3
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a solution of 2.00 g (5.4 mmoles) of 21,21-dimethoxy-20-methylpregna-1,4,6-trien-3-one in 70 ml of methanol were added a 10 wt % solution of sodium hydroxide in methanol (0.55 ml) and 3.04 ml of a 30 wt % aqueous solution of hydrogen peroxide (containing 29.8 mmoles of hydrogen peroxide) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was worked up in the same manner as Example 6 to recover 1.56 g of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3-one (yield: 75%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](B(O)O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:22])=[CH:17][CH:16]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:22])=[CH:17][CH:16]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2ccc3c(c2)OCCO3)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from 2,3-Dihydro-1,4-benzodioxin-6-yl boronic acid and (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone. MS (ES+) 393.2
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(O)(=O)C.[Br:22]N1C(=O)CCC1=O.O>[Cl-].[Na+].O>[Br:22][C:6]1[S:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[C:3]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[C:2]=1[CH3:1]
Reactant: COC(=O)c1scc(C)c1NC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1sc(Br)c(C)c1NC(=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a stirred mixture of methyl 4-methyl-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (11.7 g, 43.8 mmol) and acetic acid (150 mL) was added 1-bromopyrrolidine-2,5-dione (15.6 g, 88.0 mmol) at room temperature. Then, this mixture was stirred at 80° C. for 6 h. After cooling to room temperature, the mixture was poured into water (600 mL) and brine (300 mL). The precipitate was collected by filtration, washed with water, dried under vacuum to afford the title compound (9.40 g, 62%) as a white solid:
Reaction SMILES: C(N(CC)CC)C.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[NH2:15][CH2:16][C:17]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:32][CH3:33])[C:21]([O:30][CH3:31])=[N:22]2>COC(C)(C)C>[CH3:31][O:30][C:21]1[C:20]([O:32][CH3:33])=[N:19][C:18]2[C:23](=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:17]=2[CH2:16][NH:15][C:11](=[O:12])[CH2:10][CH2:9][C:8]([OH:13])=[O:14])[N:22]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COc1nc2cc([N+](=O)[O-])cc(CNC(=O)CCC(=O)O)c2nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
55 μl (0.397 mmol) of triethylamine and 40 mg (0.397 mmol) of succinic anhydride are added to a suspension of 100 mg (0.378 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitro-quinoxaline in 2 ml of tert-butyl methyl ether and the mixture is stirred for 3 hours at room temperature. The mixture is then filtered and the residue is washed twice with tert-butyl methyl ether. The filter residue is chromatographed on silica gel with dichloromethane/methanol/acetic acid (95:4.5:0.5). The title compound is obtained in the form of a beige powder.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.Cl.[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:35][CH:34]=4)=[O:3])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 18.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-methylsulfonylaniline hydrochloride (71.0 mg) were used to obtain ((2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methylsulfonylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (13.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([C:25]([F:28])([F:27])[F:26])[NH:22][CH2:21][CH2:20]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[C:25]([F:26])([F:28])[F:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Fc1cccc2c1C(C(F)(F)F)NCC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cccc(F)c2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH:24]1(O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH:24]1([O:8][C:6]2[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OC1CCCCC1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OC2CCCCC2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, cyclohexanol and DBU in DME. ES-MS m/e (%): 305 (M+H+, 100), 223 ([M+H—C6H10]+, 80).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH:14]([C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[C:23]2[CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=2[O:37][CH3:38])=[CH:18][CH:17]=1)=[O:15]>CN(C)C=O>[C:14]([C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[C:23]2[CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=2[O:37][CH3:38])=[CH:18][CH:17]=1)([OH:3])=[O:15]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C=O)cc23)c(OC)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cccc3ccc(C(=O)O)cc23)c(OC)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of Jones reagent (1.53 ml) [prepared from 26.72 g chromium trioxide in 23 ml concentrated sulfuric acid, diluted with water to 100 ml] was added to a solution of methyl 4-(7-formylnaphth-1-yl-methyl)-3-methoxybenzoate (409 mg) in dimethylformamide (12 ml, distilled over CaH2). The mixture was stirred for 1 h and was partitioned between methylene chloride and 1N HCl. The organic layer was washed (1N HCl (twice), brine), dried (MgSO4) and evaporated. The residue was triturated with ether, ground to a powder and vacuum dried at 120° C. for 12 h to afford methyl 4-(7-carboxynaphth-1-ylmethyl)-3-methoxybenzoate (347 mg, 81%) as a pale yellow solid; mp 229.0°-230° C.; MS(CI), m/e=351(M+H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[CH3:9][O:10][C:11]1[N:12]=[N+:13]([O-:21])[C:14]([CH3:20])=[CH:15][C:16]=1[N+]([O-])=O.O>C(Cl)Cl>[CH3:9][O:10][C:11]1[N:12]=[N+:13]([O-:21])[C:14]([CH3:20])=[CH:15][C:16]=1[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: COc1n[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1n[n+]([O-])c(C)cc1OCC(F)(F)F
Temperature: 55 °C
Reaction time: 1 h

Procedure:
2,2,2-Trifluoroethanol (3 ml) was initially charged at RT and admixed with sodium hydride (403 mg) in portions while cooling with ice. Thereafter, the reaction mixture was heated to 55° C. for 2 h and then 3-methoxy-6-methyl-4-nitropyridazine 1-oxide solution (500 mg, dissolved in 3 ml of 2,2,2-trifluoroethanol) was added dropwise. After stirring at RT for 1 h, the mixture was heated to 55° C. for 2.5 h. After standing at RT overnight, the mixture was admixed with water and DCM. After removing the DCM phase, the aqueous phase was extracted three times with DCM and the combined DCM phases were dried over sodium sulfate, filtered and concentrated. 571 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]=2[CH:14]=1.Br[CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH3:19])=[CH:17][N:6]2[C:5]3[N:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:13]=3[C:12]3[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8][C:7]2=3)=[CH:21][CH:22]=1
Reactant: CC(=CBr)c1ccc(F)cc1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)cnc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a degassed solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (201 mg, 1.0 mmol), 1-(2-bromo-1-methyl-vinyl)-4-fluoro-benzene (279 mg, 1.3 mmol), potassium phosphate (530 mg, 2.5 mmol) in DMF (4 mL), L-proline (28 mg, 0.25 mmol) and cuprous iodide (47 mg, 0.25 mmol) were added. The reaction mixture was stirred at 120° C. for 8 h. The reaction mixture was cooled to RT, diluted with water (20 mL) and extracted with EtOAc (4×20 mL). The organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by silica gel flash chromatography to yield 9-[2-(4-fluoro-phenyl)-propenyl]-3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene. 1H NMR (CDCl3, freebase) δ (ppm): 8.1 (s, 1H), 7.57 (m, 3H), 7.07 (t, 2H), 6.92 (s, 1H), 3.62 (s, 2H), 2.8 (s, 4H), 2.6 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][CH2:13][CH3:14])[N:6]=[CH:7]2.[I-].CS[C:18]1[S:19][CH2:20][C@@H:21]2[CH2:30][C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][N+:22]=12>>[CH2:12]([C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:18]1[N:22]3[CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[CH2:30][C@H:21]3[CH2:20][S:19]1)[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH3:14]
Reactant: CCCc1cc2c(N)cccc2cn1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: CCCc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Yield: 97.3 %

Procedure:
By following the procedure of Example 3 but using 5-amino-3-propylisoquinoline (0.18 g) and (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (0.35 g) as starting materials, (S)-3-[(3-propylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (0.35 g) is obtained in a crude form, which is purified by chromatography on a column (diameter of the column: 0.7 cm) containing silica (6 g) by eluting with methylene chloride and collecting the eluate in 20 cc fractions.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][F:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[C:21]#[N:22]>C1COCC1.O>[F:1][CH2:2][CH:3]([CH2:4][F:5])[O:6][C:24]1[CH:23]=[C:20]([CH:19]=[CH:18][C:25]=1[N+:26]([O-:28])=[O:27])[C:21]#[N:22]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: OC(CF)CF
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc([N+](=O)[O-])c(OC(CF)CF)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,3-Difluoro-propan-2-ol (4.2 g) was dissolved under argon in THF (250 ml) and cooled to 0° C. LiHMDS (28 ml) was added to the mixture and stirred at rt for 1 hour. Then the mixture was cooled to 0° C. and 3-fluoro-4-nitrobenzonitrile (1.95 ml) was added in portions and stirred for 2 hours. The mixture was poured in water and extracted with DCM. The organic layer was washed with water, dried and concentrated.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[N:6])[CH3:2].[N+:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])#[C-:11].CCOCC>COCCOCCOC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]1[N:6]=[CH:11][NH:10][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CCOC(C#N)OCC
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCOC(OCC)c1nc[nH]c1C(=O)OC
Temperature: 75 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a stirred suspension of 30-35% KH (7.90 g) in 40 mL anhydrous diglyme at −20° C. was added a solution of diethoxyacetonitrile (Intermediate 1A, 6.20 g, 46.6 mmol) and methyl isocyanoacetate (4.96 g, 65.2 mmol) in 25 mL of anhydrous diglyme. The resulting mixture was heated to 70-80° C. and stirred overnight. The mixture was cooled to room temperature and quenched with saturated NH4Cl solution. DCM was added and the layers were separated. The mixture was further extracted with DCM. The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give brown oil. Cold ether was added to the residue and the resulting white precipitate was filtered, washed with cold ether and dried to give the desired product Intermediate 1B (5.65 g, 53%) as a white solid.