Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)=[CH:6][CH:5]=1.O=[C:28]([CH3:42])[CH2:29][CH2:30][N:31]1C(=O)C2C(=CC=CC=2)C1=O>>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH:19]3[CH2:20][CH2:21][N:22]([CH:28]([CH3:42])[CH2:29][CH2:30][NH2:31])[CH2:23][CH2:24]3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C2(c3ccc(OC(F)(F)F)cc3)Oc3ccccc3O2)CC1

Procedure:
Using general procedure B with the above amine (260 mg, 0.712 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (309 mg, 1.42 mmol) and then using general procedure D gave 3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (193 mg, 63% over 2 steps).
Reaction SMILES: N(OC(C)(C)C)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[Cl:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([C:21]2[C:25]([Cl:26])=[C:24]([C:27]([F:30])([F:29])[F:28])[N:23]([CH3:31])[N:22]=2)=[CH:16][C:14]=1N.O>FC(F)(F)C(O)=O>[Cl:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([C:21]2[C:25]([Cl:26])=[C:24]([C:27]([F:29])([F:30])[F:28])[N:23]([CH3:31])[N:22]=2)=[CH:16][C:14]=1[N:8]=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1nc(-c2cc(N=[N+]=[N-])c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reaction time: 2 h

Procedure:
0.46 g (4.5 mmol) of tert-butyl nitrite and 0.3 g (4.5 mmol) of sodium azide were added to a solution of 1 g (3 mmol) of 2-chloro-5-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-4-fluoroaniline in 20 ml of trifluoroacetic acid. The mixture was subsequently stirred for 2 hours and then admixed with 50 ml of water. The resulting product was extracted from the aqueous phase using 100 ml of methyl tert-butyl ether. The extract was washed with 10% strength aqueous sodium hydroxide solution, then dried over magnesium sulfate and finally concentrated. The crude product was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1:1). Yield: 0.7 g; 1H NMR (400 MHz; in (CD3)2SO): δ[ppm]=4.10 (s,3H), 7.53 (d,1H), 7.77 (d,1H).
Reaction SMILES: [OH:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]1([OH:15])[C:5]1[CH:16]=[CH:17][C:18]([CH:20]([CH3:22])[CH3:21])=[CH:19][C:4]=1[O:3]2.O.NN.[OH-].[K+]>C(O)COCCO>[OH:15][C:6]1([C:5]2[CH:16]=[CH:17][C:18]([CH:20]([CH3:21])[CH3:22])=[CH:19][C:4]=2[OH:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1]
Reactant: CC(C)c1ccc2c(c1)OC1(O)c3ccccc3C(=O)C21O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CC(C)c1ccc(C2(O)Cc3ccccc3C2=O)c(O)c1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 6439.8 %

Procedure:
To a solution of 4b,9b-dihydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (1.0 g, 3.3 mmol) in diethylene glycol (10 ml) were added with hydrazine hydrate (80%, 0.36 g, 9.6 mmol), followed by stirring at 150° C. for 15 min. The reaction mixture was added potassium hydroxide (360 mg, 6.4 mmol), and stirred at 165-170° C. for 1 hrs. The reaction mixture was extracted with ethylacetate, and purified using column chromatography (20% ethylacetate in hexane) to afford the title compound (60 g, 6.5%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=3[CH:8]=2)[NH:3]1.[H-].[Na+].CI.[C:26](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:26][N:3]1[C:4]2[C:9](=[CH:8][C:7]3[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16][C:6]=3[CH:5]=2)[CH2:10][CH2:11][C:2]1=[O:1]
Reactant: O=C([O-])O
Reactant: CCOC(=O)N1CCc2cc3c(cc2CC1)NC(=O)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2cc3c(cc2CC1)N(C)C(=O)CC3
Reaction time: 1 h

Procedure:
287 mg of ethyl 2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate was dissolved in 5 ml of DMF, and 65 mg of 60% sodium hydride was added thereto in an ice-bath, followed by stirring for 1 hour. 0.3 ml of methyl iodide was added thereto, followed by stirring at room temperature for 3 hours. Then, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 94 mg of ethyl 1-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH2:6])[CH2:4][OH:5].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH:6][CH:3]([CH2:4][OH:5])[CH2:2][OH:1])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: NC(CO)CO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NC(CO)CO)n4)cc3)cc12

Procedure:
Using 2-hydroxy-1-hydroxymethyl-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 457 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][C@@H:15]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.CCOC(C)=O.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][C@@H:15]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:11][N:10]=[CH:9]2)=[CH:42][CH:43]=1)#[N:2]
Reactant: [H][H]
Reactant: CS(=O)(=O)CC[C@@H](CN(Cc1cccc(Cl)c1)C(=O)OCc1ccccc1)NCc1cncn1Cc1ccc(C#N)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CC[C@@H](CNCc1cccc(Cl)c1)NCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
To a solution of the product from Step F (163 mg, 0.262 mmol) in 3 mL of methanol and 3 mL of EtOAc was added at room temperature 10% palladium on carbon (10 mg). A balloon of hydrogen gas was introduced to the solution via syringe needle, and the reaction was stirred for ca. 20 minutes. The solution was filtered through celite to remove the catalyst, then concentrated in vacuo. The resulting product was purified by silica gel chromatography (4% MeOH/CH2Cl2 with 1% NH4OH) to provide the titled compound (63 mg).
Reaction SMILES: [C:1]([C:5]1(C(OCC)=O)[O:9][NH:8][CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.[O:18]1CCC[CH2:19]1>C(O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:19][OH:18])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(C(C)(C)C)C=CNO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1.83 g of ethyl 5-t-butyl-isoxazole-5-carboxylate was dissolved in 18 ml of tetrahydrofuran, and 0.70 g of sodium borohydride in 10 ml of ethanol was then added. The mixture was stirred at room temperature for 10 hours. After 5 ml of water was added, the reaction mixture was concentrated to 5 ml under reduced pressure. The concentrated solution was extracted with methyl-t-butyl ether. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 0.62 g of (5-t-butyl-isoxazol-3-yl)methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C@H:7]2[C@H:11]([OH:12])[CH2:10][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)Cl>[CH3:20][NH:21][C:22]([O:12][C@H:11]1[C@H:7]([O:6][C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:10]1)=[O:23]
Reactant: CN(C)C(=O)N1C[C@@H](O)[C@H](Oc2ccc(Cl)cc2)C1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)O[C@@H]1CN(C(=O)N(C)C)C[C@H]1Oc1ccc(Cl)cc1

Procedure:
A solution of 1.0 g. (0.003 mole) of trans-3-(4-chlorophenoxy)-4-hydroxy-N,N-dimethyl-1-pyrrolidine carboxamide and 1.0 g. (0.02 mole) of methylisocyanate in 20 ml. of methylene chloride was let stand at ambient temperature for 48 hr. The solution was concentrated to give an oil which crystallized upon standing. The solid was recrystallized from benzene-cyclohexane to yield 0.6 g. (50%) of white solid, m.p. 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](=[S:41])[NH2:40]>CC(N(C)C)=O.CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:41][C:39]([C:38]([CH3:43])([CH3:42])[CH3:37])=[N:40][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a solution of N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (1.0 g, 2.4 mmol) in 25 mL DMA, NBS (0.420 g, 2.4 mmol) was added and the solution was allowed to stir 15 minutes at rt. 2,2-Dimethylpropanethioamide (0.277 g, 2.359 mmol) was then added and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with water ×3. The organic layer was dried over MgSO4 and filtered. The organic solution was evaporated onto silica gel and chromatographed. 0-50% EtOAc in DCM to give the title compound (1.01 g, 81% yield). ES-LCMS m/z 521.1 (M+H).
Reaction SMILES: [CH:1]1([C@H:4]2[O:10][C@H:5]2[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.C(OC)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CO.O>[CH:1]1([C@H:4]([N:15]=[N+:16]=[N-:17])[C@@H:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1O[C@@H]1C1CC1
Agent: [Na+]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: COC(=O)[C@H](O)[C@@H](N=[N+]=[N-])C1CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
(5)To a solution of 2.89 g of methyl (2R,3R)-3-cyclopropyl-2,3-epoxypropionate in 112.5 ml of methanol-water (8:1) are added 14 ml of methyl formate and 16.60 g of sodium azide. Then, the reaction mixture is stirred at 50° C. overnight. The reaction mixture is cooled to room temperature and evaporated to remove methanol. The residue is dissolved in ethyl acetate. The solution is washed with brine and dried. The solvent is removed in vacuo. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:l) to give 2.61 g of methyl (2R,3S)-3-cyclopropyl-3-azido--2-hydroxypropionate.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O.C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(F)c2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 2.1 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added ethanol 0.6 mL, water 0.3 mL, 3-fluorophenylboronic acid 46 mg, sodium hydrogen carbonate 69 mg and tetrakis(triphenylphosphine)palladium(0) 16 mg at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, tetrakis(triphenylphosphine)palladium(0) 16 mg were added, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, toluene and saturated sodium hydrogen carbonate aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-(3-fluorophenyl)benzoate.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:10]=1[CH2:11]O.S(Cl)([Cl:23])=O.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:10]=1[CH2:11][Cl:23]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CCl
Temperature: 47.5 °C

Procedure:
Under nitrogen, 27.9 mL of triethylamine was added to the concentrated solution of 2,3-dichloro-6-nitrobenzylalcohol (compound XI) prepared in the previous step. To this solution, 14.6 mL of thionyl chloride was added via an addition funnel over 15 minutes. Following addition, the solution is heated to 45-50° C. for 18 hours, then cooled to room temperature under nitrogen. Water and toluene are added to the reaction mixture and the mixture filtered. The filtrate is diluted with water, and the aqueous layer removed. The organic layer is washed with water (4×40 mL), and dried by azeotropic distillation. The solution is concentrated to give 1,2-dichloro-3-chloromethyl-4-nitrobenzene (compound (VIII), which could be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: COc1ccccc1C=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1C=[N+]([O-])C(C)(C)C
Temperature: 5 °C

Procedure:
To a suspension of 2-methoxybenzaldehyde (622.4 mg, 4.57 mmol), 1,1-dimethylnitroethane (942.7 mg, 9.14 mmol) and zinc (896.3 mg, 13.7 mmol) in ethanol (15 ml) was added acetic acid (944.8 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. After the mixture was cooled to 5° C., zinc acetate was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1).
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=[C:32]2O.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([O:41][CH2:42][CH3:43])[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: CCOc1cc(O)c2cc(Br)c(OC)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(Br)c(OC)cc2n1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 1-t-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (25.0 g, 53.8 mmol), 6-bromo-2-ethoxy-7-methoxyquinolin-4-ol (16.1 g, 53.8 mmol) and Cs2CO3 (52.6 g, 162 mmol) in NMP (300 mL) was stirred at 75° C., under N2, for 2 hours. At 22° C., the reaction was diluted with water (500 mL) and extracted with EtOAc (3×500 mL). The combined EtOAc layers were washed with water (3×100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 0 to 50% EtOAc in hexane, to give the title product. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H); 7.16 (s, 1H); 6.02 (s, 1H); 5.05 (m, 1H); 4.49 (m, 3H); 4.00 (s, 3H); 3.91 (m, 2H); 3.78 (s, 3H); 2.67 (m, 1H); 2.37 (m, 1H); 1.47 (s, 3H); 1.44 (s, 9H) ppm. LRMS (ESI) m/z 525.0 [(M+H)+; calcd for C23H30BrN2O7: 298.0].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[C:5]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:7]3[CH2:8][N:9]=[CH:10][C:11]([CH:12]=1)=[C:6]23.C[I:24].[C:25]1(C[Mg]Cl)C=CC=CC=1>>[I-:24].[CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[C:5]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:7]3[CH2:8][N+:9]([CH3:25])=[CH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: COc1cc2c3c(c1OC)CCc1ccccc1C3CN=C2
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CI
Product: COc1cc2c3c(c1OC)CCc1ccccc1C3C[N+](C)=C2
Product: [I-]

Procedure:
By following serially the procedure of step (a) of example 5 and the procedure of example 6 and selecting 5,6-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline as the starting material of formula II, methyl iodide as the organohalide and phenylmethyl magnesium chloride as the Grignard reagent, (3,12b-trans)-5,6-dimethoxy-2-methyl-3-(phenylmethyl)-1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline, mp 154°-156° C., NMR (CDCl3) δ2.4 (s, 3H), 3.77 & 3.85 (2s, 6H), 6.5 (s, 1H), 7.2 (m, 9H), was obtained via 5,6-dimethoxy-2-methyl-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinolinium iodide, mp 195°-210° C. (dec), NMR (DMSO-d6) δ 3.83 (s, 3H), 3.88 (s, 3H), 3.97 (s, 3H), 4.42 (m, 2H), 5.18 (m, 1H), 7.10 (m, 4H), 7.38 (s, 1H), 9.17 (s, 1H).
Reaction SMILES: [C:1]([O:4][N:5]1[C:9]([CH2:10]O)=[CH:8][N:7]=[C:6]1[CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>C(Cl)Cl>[ClH:17].[C:1]([O:4][N:5]1[C:9]([CH2:10][Cl:17])=[CH:8][N:7]=[C:6]1[CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: C=CCc1ncc(CO)n1OC(C)=O
Solvent: ClCCl
Product: C=CCc1ncc(CCl)n1OC(C)=O
Product: Cl

Procedure:
React allyl-5-hydroxymethylimidazol-1-yl acetate with excess thionyl chloride in CH2Cl2 at ice bath temperatures for about 8 hours to form the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[OH:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[OH:26])=[C:11]([C:41]3[CH2:42][CH2:43][O:38][CH2:39][CH:40]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-yl)(4-(trifluoromethyl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: CC(C)(C)C([O:5][CH:6]1[CH:13]2[CH:9]([CH2:10][CH:11]([CH:14]=O)[CH2:12]2)[C:8](=[O:16])[CH:7]1[C:17]1[C:22]([CH2:23][CH3:24])=[CH:21][C:20]([CH3:25])=[CH:19][C:18]=1[CH2:26][CH3:27])=O.C([O-])=O.[Na+].Cl.[NH2:35]O.O>C(O)=O.C(OCC)(=O)C>[CH2:26]([C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH2:23][CH3:24])[C:17]=1[CH:7]1[C:6](=[O:5])[CH:13]2[CH:9]([CH2:10][CH:11]([C:14]#[N:35])[CH2:12]2)[C:8]1=[O:16])[CH3:27]
Reactant: NO
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(C=O)CC2C1OC(=O)C(C)(C)C
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(C#N)CC2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.91 g (2.30 mmol) of 2-(2,6-diethyl-4-methylphenyl)-5-formyl-3-oxooctahydropentalen-1-yl 2,2-dimethylpropanoate (Example I-b-2), 0.78 g (11.48 mmol) of sodium formate and 0.80 g (11.48 mmol) of hydroxylamine hydrochloride in 30 ml of formic acid are heated at reflux for 72 h. 50 ml of water are then added, and the mixture is stirred at room temperature for 1 h, taken up in ethyl acetate, washed twice with water, dried (magnesium sulphate) and concentrated using a rotary evaporator. The residue is chromatographed on silica gel (mobile phase ethyl acetate/hexane 1:6). This gives 0.31 g (44%) of the desired compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C1CCN2C(=NCCC2)CC1.[Li+].[Cl-].[F:25][C:26]1[CH:27]=[C:28]([C:39]23[CH2:46][CH2:45][C:42]([CH2:47][CH2:48][CH:49]=O)([CH2:43][CH2:44]2)[CH2:41][O:40]3)[CH:29]=[C:30]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:31]=1>CC#N>[F:25][C:26]1[CH:27]=[C:28]([C:39]23[CH2:44][CH2:43][C:42]([CH2:47][CH2:48]/[CH:49]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])([CH2:45][CH2:46]2)[CH2:41][O:40]3)[CH:29]=[C:30]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:31]=1
Reactant: O=CCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)/C=C/CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A 0° C. mixture of trimethyl phosphonoacetate (0.209 mL, 1.45 mmol), DBU (0.218 mL, 1.45 mmol) and LiCl (0.061 g, 1.45 mmol) in MeCN (5 mL) was stirred for 30 min under N2, after which 3-(1-(3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (0.35 g, 0.966 mmol) in MeCN (5 mL) was added. The reaction was stirred for 2 h at rt, then was concentrated in vacuo. The residue was diluted with Et2O, and then washed successively with 1N aq. HCl, sat. aq. NaHCO3, and brine, dried (MgSO4), and concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient from 0% to 50% EtOAc/hexane over 20 min) to give the title compound (0.30 g, 0.717 mmol, 74.2% yield) as a white solid. 1H NMR (CDCl3) δ: 6.97 (dt, J=15.6, 6.8 Hz, 1H), 6.87 (t, J=1.8 Hz, 1H), 6.75 (ddd, J=10.1, 2.3, 1.4 Hz, 1H), 6.68 (dt, J=10.5, 2.3 Hz, 1H), 5.85 (dt, J=15.6, 1.6 Hz, 1H), 5.40 (t, J=3.2 Hz, 1H), 3.89 (ddd, J=11.3, 10.0, 3.1 Hz, 1H), 3.84-3.81 (m, 2H), 3.75 (s, 3H), 3.62 (dtd, J=11.4, 4.1, 1.4 Hz, 1H), 2.22-2.14 (m, 2H), 2.05-1.98 (m, 4H), 1.88-1.82 (m, 2H), 1.75-1.59 (m, 8H), 1.36-1.30 (m, 2H); 19F NMR (CDCl3) δ: −112.1.