Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:8]([CH2:12][CH3:13])[C@@H:9](N)[OH:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC1(C)[N:20]([O])C(C)(C)CCC1.[Br-].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O>[C:4]([O:3][C:1]([C@:8]([NH2:20])([CH2:12][CH3:13])[CH:9]=[O:10])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: CCC(C(=O)OC(C)(C)C)[C@@H](N)O
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 77 %

Procedure:
To a solution of (S)-2-Boc-aminobutanol (50 g; 264 mmol) in dichloromethane (500 mL) and water (350 mL) were added at 20° C. TEMPO (0.01 eq), sodium bromide (1 eq) and sodium hydrogencarbonate (3 eq). The reaction mixture was stirred at 0° C. and diluted bleach (1.3 eq, 450 mL) was added over 40 min. The reaction mixture was stirred for 30 min. at 0° C. and then quenched with aq. thiosulfate. After decantation and extractions (dichloromethane), the organic phase was washed with brine, dried and concentrated in vacuo to dryness, giving (S)-2-(tert-butoxycarbonyl)-amino-butyraldehyde as a low-melting solid (38.1 g; yield: 77%). C9H17NO3; MW=187.2; Tmelt=44° C.; NMR (CDCl3, ppm): 0.97 (t, J=7 Hz, 3H), 1.45 (s, 9H), 1.68 (m, 1H), 1.91 (m, 1H), 4.20 (lq, J=6.5 Hz, 1H), 5.09 (1s, 1H (mobile)) and 9.59 (s, 1H); SM (EI; m/z): 158 (M+—CHO), 102, 57.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)=[S:11])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:20][O:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=1
Reactant: COc1cc(NC(=S)NC(=O)c2ccccc2)cc(-c2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(NC(N)=S)cc(-c2ccccc2)c1
Yield: 87.3 %

Procedure:
1-Benzoyl-3-(5-methoxy-biphenyl-3-yl)-thiourea (183 mg, 0.51 mmol) in methanol (5 ml) are treated with sodium methoxide (5.4M in methanol, 0.14 ml) and the formed precipitate is filtered off. Washing with methanol yields the product (115 mg, 88%) as off-white powder. MS: m/e=258 (M+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)(=[O:21])[CH3:20]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(O)c2cc(O)ccc2oc1=O
Reactant: CC(=O)OCCCCBr
Product: CCCCOc1c(O)c2cc(OCCCCOC(C)=O)ccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-butoxy-4,6-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 4-bromobutyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-butoxy-4-hydroxy-6-(4-acetoxybutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH2:5][O:6][C:7]2=[O:8].[Br:17]N1C(=O)CCC1=O.N(CCCC#N)=NCCCC#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH:5]1[C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[C:7](=[O:8])[O:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(c(OC)c1OC)COC2=O
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2c(c(OC)c1OC)C(Br)OC2=O

Procedure:
4,5,6-Trimethoxyphthalide (11.4 gms; 0.05 mole), N-bromosuccinimide (8.9 gms; 0.05 mole) and azobisbutyronitrile (0.1 gms) were refluxed gently in dry carbon tetrachloride (200 mls) for 2 hours. The solution was cooled, the succinimide filtered off and the solvent removed in vacuo, leaving a yellowish solid which fumed in the air.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[S:11][CH2:12][CH2:13][N:14]=2)=[O:8])=[C:5]([O:17]COC)[CH:4]=1>Cl.CO>[OH:17][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:16]=[CH:15][C:6]=1[C:7]([NH:9][C:10]1[S:11][CH2:12][CH2:13][N:14]=1)=[O:8]
Reactant: COCOc1cc(OC)ccc1C(=O)NC1=NCCS1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)NC2=NCCS2)c(O)c1

Procedure:
To 8.87 g of the thus produced 2-(4-methoxy-2-methoxymethoxybenzoylamino)thiazoline was added 200 ml of aqueous hydrochloric acid-methanol, and the mixture was heated under reflux for 15 minutes. The solvent was distilled off in evacuated atomosphere, and to the residue was added saturated aqueous solution of sodium bicarbonate. The mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off in evacuated atomosphere and the residue was recrystallized from benzene to produce 6.39 g of 2-(2-hydroxy-4-methoxybenzoylamino)thiazoline.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[S:8][C:9](Cl)=[N:10][N:11]=1>C(O)C>[NH2:6][C:7]1[S:8][C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[N:10][N:11]=1
Reactant: Nc1nnc(Cl)s1
Reactant: C1CCNC1
Solvent: CCO
Product: Nc1nnc(-n2cccc2)s1
Temperature: 40 °C

Procedure:
Pyrrolidine (200 μl) was added to a solution of 2-amino-5-chloro-1,3,4-thiadiazole (60 mg) in ethanol (2 ml) and the mixture heated in a sealed vial at 40° C. for 6 hours. The precipitate was filtered off and washed with a little methanol to give 2-amino-5-pyrrol-1-yl-1,3,4-thiadiazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O)C.O.NN>C1COCC1.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1CN1CCOCC1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(F)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 4-(5-fluoro-2-nitrobenzyl)morpholine (240 mg; 1.0 mmol) in THF:ethanol mixture (1:1) (40 mL) was added a catalytical amount of Raney-Nickel and hydrazine hydrate (6.0 mmol). The mixture was stirred for 30 minutes at ambient temperature, then filtered through a Celite pad and the filtrate was evaporated to provide the title compound (208 mg, 99%), which was used in further reactions without purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: OCC1CCCN1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2CO)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
20 g of 5-fluoro-2-nitrotoluene, 14.3 g of 2-pyrrolidine methanol and 20 g of potassium carbonate were added to 100 ml of dimethylformamide. They were stirred at 100° C. for 2 h. After leaving to cool, the reaction mixture was poured into water. After extraction with ethyl acetate, the extract was washed with water, concentrated and recrystallized from acetonitrile to obtain 26 g of 2-hydroxymethyl-N-(3-methyl-4-nitrophenyl)pyrrolidine (d) as yellow crystals.
Reaction SMILES: [CH3:1][C@@H:2]([NH:10][C:11]([C:13]1[O:14][C:15]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=2[C:17](=[O:19])[CH:18]=1)=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1>[Ni].C(O)C>[CH3:1][C@@H:2]([NH:10][C:11]([CH:13]1[CH2:18][C:17](=[O:19])[C:16]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:15]=2[O:14]1)=[O:12])[C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: C[C@@H](NC(=O)c1cc(=O)c2cc(F)ccc2o1)c1ccc(Cl)cc1
Agent: [Ni]
Solvent: CCO
Product: C[C@@H](NC(=O)C1CC(=O)c2cc(F)ccc2O1)c1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
Raney nickel (400 mg) was added to a solution of (-)-N-[(R)-α-methyl-p-chlorobenzyl]-6-fluoro-4-oxo-4H-1-benzopyran-2-carboxamide (1.00 g, 2.89 mmol, obtained in Example 7) in ethanol (20 ml) and the mixture was hydrogenated for 5 hour at a temperature of 55°-60° C. under H2 atomosphere (4 kg/cm2) with stirring. It was determined that the (+)-isomer/(-)-isomer ratio of the reduction product was 2.7/1 (46% d.e.) by 1H-NMR analysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=1.[H][H]>[Pd].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1N
Yield: 88.7 %

Procedure:
Five-percent palladium on carbon (2.53 g) was added to a solution of 10.0 g of N-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide in 150 ml of methanol, and the mixture was stirred in a hydrogen atmosphere at 60° C. for 15 hours. The solid material was separated through filtration, and the filtrate was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 7:3) to give 8.02 g of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:18]3[O:17][C:16](=O)[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[NH4+:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:18]3[NH:22][C:16](=[O:17])[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)c(F)c(F)c1)CC2
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1cc(F)c(F)c(F)c1
Yield: 106.2 %

Procedure:
A solution of 7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (1.23 g, 4.34 mmol) in concentrated ammonium hydroxide (75 mL, 1926 mmol) was heated at 100° C. in a high-pressure (350 mL) vessel overnight. The reaction mixture was cooled and concentrated in vacuum to give crude 7-(3,4,5-trifluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (1.3 g, 4.61 mmol, 106% yield). LC-MS (M+H)+=283.0.
Reaction SMILES: BrC1C=CC=CC=1C(O)=O.S(Cl)(Cl)=O.S1C=CC=C1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)=[O:28].[BH4-].[Na+].Cl>C(=S)=S.C(O)C.O.CC(C)=O.CN(C)C=O>[Br:24][C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[CH:27]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[OH:28]
Reactant: O=C(c1cccs1)c1ccccc1Br
Agent: Cl
Agent: O=C(O)c1ccccc1Br
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: OC(c1cccs1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirring mixture of 154.8 g of 2-bromobenzoic acid, 107.1 g of thionyl chloride and 0.2 ml of dimethylformamide is heated on a steam bath for 45 minutes and then any excess thionyl chloride is distilled off under reduced pressure leaving the crude acid chloride. A mixture of the acid chloride and 60 g of thiophene in 255 g of carbon disulfide is added dropwise to a suspension at 15° C of 100 g of aluminum chloride and 300 g of carbon disulfide. After total addition the mixture is stirred at ambient temperature for 3 hours and then allowed to stand for 16 hours. The stirring mixture is now successively refluxed on a steam bath for 3.5 hours, cooled to ambient temperature and poured over 1 l. of ice followed by dilution with 0.5 l. of water. The biphasic mixture is strained through glass wool to remove any precipitate and then permitted to separate. The aqueous phase is extracted with three 600 ml portions of ether. The ether extracts are combined with the carbon disulfide phase and this mixture is washed with two 500 ml portions of an aqueous 5% sodium carbonate solution followed by washing with two 500 ml portions of water. The organic solution is dried, filtered and then concentrated under reduced pressure leaving a dark oil. The oil is distilled leaving as the main fraction, b.p. 139°-145° C, a green colored oil of 2-(2-bromobenzoyl)thiophene. A solution of 15.0 g of 2-(2-bromobenzoyl)thiophene in 15 ml of absolute ethanol is carefully added with stirring and cooling to a mixture of 2.3 g of sodium borohydride in 40 ml of absolute ethanol. After total addition 15 ml of absolute ethanol is added. The reaction mixture is stirred for 16 hours at ambient temperature and then 50 ml of acetone is added with stirring and the mixture is permitted to stand for 24 hours at ambient temperature. The mixture is poured into 500 ml of water and the resulting mixture acidified with a 5% hydrochloric acid solution causing the mixture to become cloudy. The cloudy mixture is extracted with three 125 ml portions of chloroform which are combined and washed with ten 200 ml portions of water. The chloroform solution is dried and filtered and the chloroform evaporated off leaving α-(2-bromophenyl)-2-thiophenemethanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and aniline (11.0 mg, 0.12 mmol). The title compound was obtained as a yellow solid (5.0 mg, 11% yield). MS m/z: 425.96, 427.95 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 49 %

Procedure:
As described for Example 4, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (90 mg, 0.32 mmol) was converted, using 4-fluorobenzonitrile instead of 4-fluorobenzotrifluoride, to the title compound (60 mg, 49%) which was obtained as a white solid. MS: m/e=381.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:44][C:45]1([F:50])[CH2:49][CH2:48][NH:47][CH2:46]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:47]3[CH2:48][CH2:49][C:45]([F:50])([F:44])[CH2:46]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC1(F)CCNC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Agent: Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(F)(F)C3)(CC1)CC2
Yield: 85.8 %

Procedure:
In a similar manner to Example 13, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 3,3-difluoropyrrolidine hydrochloride (18.7 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(3,3-difluoropyrrolidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.8 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][C@@H:9]([OH:11])[C@H:8]2[C@@H:6]1[C@:7]2([F:16])[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].CC1(C)N([O])C(C)(C)CCC1.C(=O)([O-])O.[Na+].Cl[O-].[Na+]>O.ClCCl>[C:1]([O:4][C@H:5]1[CH2:10][C:9](=[O:11])[C@H:8]2[C@@H:6]1[C@:7]2([F:16])[C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@]1(F)[C@@H]2[C@H]1[C@@H](OC(C)=O)C[C@H]2O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@]1(F)[C@@H]2[C@@H](OC(C)=O)CC(=O)[C@@H]21
Reaction time: 1 h

Procedure:
A dichloromethane (dehydrated, 5 mL) solution of 946 mg (4.07 mmol) of the compound of the formula 3 was cooled to −5° C., 14.0 mg (0.090 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 102.0 mg (1.21 mmol) of sodium hydrogen carbonate, and 2.0 mL of water were added in sequence, and 3.86 g (5.19 mmol) of a 10% sodium hypochlorite aqueous solution was then added while keeping the internal temperature between −5° C. and 0° C. After stirring at −5° C. to 0° C. for 1 hour, the mixture was separated. The organic layer was washed with 1 mL of water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 899 mg of the compound of the formula 4 was obtained as an oily substance with yellow color.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(N(CC)CC)C.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C)C=O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4ccccc4)cc3CC[C@@H]12
Yield: 74.4 %

Procedure:
Five hundred mg of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, 4 mg of palladium acetate, 20 mg of tri-o-tolylphosphine, 0.34 mL of triethylamine and 5 mL of dimethylformamide were placed in a screw capped sealable tube with a stir bar. The mixture was warmed to 60° and then 200 mg of styrene was added and the vessel was flushed with argon. The vessel was then capped and heated at 120° for 24 h. The reaction mixture was cooled, diluted with ethyl acetate and filtered and the filtrate was concentrated under vacuum. The residue was dissolved in chloroform and washed twice with water. The organic layer was dried, filtered and evaporated under vacuum to obtain 400 mg of residue, which was recrystallized from ethyl acetate to obtain the desired product. m.p. 173°-175°. FDMS m/e=331.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1CCN2C(=NCCC2)CC1>O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nccc2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccccc23)CC1
Temperature: 107.5 °C
Yield: 66 %

Procedure:
1-Chloro-isoquinoline (176 mg, 1.07 mmol), piperazine-1-carboxylic acid tert-butyl ester (420 mg, 2.26 mmol) and DBU (0.25 mL, 1.61 mmol) were added into DMP (2 mL). The mixture was heated to 105-110° C. for overnight. The residue was diluted with water and extracted with ether. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to dryness. The resulting residue was purified by column chromatography (5% to 10% ethyl acetate/hexane) to give 222 mg of the desired product 4-isoquinolin-1-yl-piperazine-1-carboxylic acid tert-butyl ester (yield: 66%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[NH2:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Nc1ccccc1I
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Nc1ccccc1-n1ccc2ccccc21

Procedure:
Using the general procedure, indole (0.117 g, 1.00 mmol) was coupled at 80° C. with 2-iodoaniline (0.263 g, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (32 μL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. The above product was identified by comparison (GC) to a previously prepared sample and the GC yield was determined to be 92%.
Reaction SMILES: C=O.[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:3][C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:36])[C@@H:20]([CH2:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=4)[CH2:19]3)[C:6]=2[CH:5]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc3ccccc3c2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
Add formaldehyde (101 μL, 1.28 mmol, 37% in water) to a solution of (S)-2-methyl-10-[3-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (525 mg, 1.16 mmol) in methylene chloride (20 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (369 mg, 1.7 mmol) and stir 1 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 550 mg (100%) of the title compound: mass spectrum (ion spray): m/z=467 (M+1), 465 (M−1). HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.