Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]=[CH:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C-]#[C-].[Li+].[Li+].[CH2:17]=[CH:18]N>O1CCOCC1>[CH3:12][N:2]([CH3:1])[CH:3]([CH2:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:17]#[CH:18]
Reactant: CCCCCC(=O)C=CN(C)C
Reactant: C=CN
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C#CC(CC(=O)CCCCC)N(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1-(dimethylamino)-1-octen-3-one (4.0 g), described in Example 37, and lithiumacetylide-ethyleneamine (4.0 g) in dry dioxane (25 ml) is stirred at room temperature for 45 min. The mixture is added to ice. The mixture is extracted with ether. The extract is dried (Na2SO4) and then evaporated. The residue is distilled to afford the title compound, b.p. 80° - 85° C.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH2:8][CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]3[N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:22][C:21]=3[NH:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)[CH2:11]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][CH2:2][C:3]([N:15]1[CH2:14][CH2:13][N:12]([C:16]2[C:25]3[N:24]=[C:23]([C:26]([F:28])([F:29])[F:27])[S:22][C:21]=3[NH:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)[CH2:11][C@@H:10]1[CH2:9][CH2:8][O:7][CH3:6])=[O:4]
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1
Reactant: O=C(Cl)CF
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(F)(F)F)nc32)CCN1C(=O)CF
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Add a solution of fluoroacetyl chloride (0.133 g, 1.38 mmol) in anhydrous dichloromethane (1-2 mL) dropwise to a 0° C. solution of (S)-10-[3-(2-Methoxy-ethyl)-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.283 g, 0.688 mmol) and diisopropylethylamine (0.240 mL, 1.38 mmol) in anhydrous dichloromethane, and stir at 0° C. for 3 hours. Concentrate the reaction under reduced pressure to afford an oil. Purify the oil by flash chromatography, eluting with a gradient of a solution of 2% 2M ammonia in methanol, in dichloromethane (0-100% in dichloromethane over 30 minutes, then 100% for 28 minutes) to give the title compound: 0.18 g (56%). Mass spectrum (APCI+, m/e): 472 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].O1C2C=CC=CC=2CC1CO.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:44][N:45]([CH3:50])[CH2:46][CH2:47][CH2:48][NH2:49]>>[CH3:44][N:45]([CH3:50])[CH2:46][CH2:47][CH2:48][NH:49][CH2:3][CH:2]1[CH2:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10]1
Reactant: C=CCc1ccccc1O
Reactant: CN(C)CCCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: OCC1Cc2ccccc2O1
Product: CN(C)CCCNCC1Cc2ccccc2O1

Procedure:
The starting diamine of formula II can be prepared according to known processes; for example starting from 2-allylphenol, which is then converted to 2,3-dihydrobenzofuran-2-yl-methanol by the action of a peracid and subsequently to the tosylate by the action of para-toluene-sulphonyl chloride, the said tosylate then being reacted with 3-(dimethylamino)-propylamine to give N,N-dimethyl-N'-(2,3-dihydro-benzofuran-2-ylmethyl)-1,3-propanediamine.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C@@H:20]2[C@H:18]1[CH2:19]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:29]>C(#N)C>[C@@H:18]12[CH2:19][C@@H:20]1[CH2:21][C@@H:22]([C:23]([O:25][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=1)=[O:29])=[O:24])[N:17]2[C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1cccc(Br)c1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
DIPEA (2.79 mL, 16.0 mmol) was added to a stirring slurry of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2.00 g, 8.80 mmol) and 2-bromo-1-(3-bromophenyl)ethanone (2.22 g, 8.00 mmol) in acetonitrile (25 mL) (the solution became clear and amber colored) and the reaction mixture was stirred overnight. The reaction was concentrated and purified via BIOTAGE® (80 g SiO2, 10-25% EtOAc/hexanes) to yield (1R,3S,5R)-3-(2-(3-bromophenyl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (3.37 g, 7.94 mmol) as a viscous light yellow oil. LC-MS retention time 1.853 min; m/z 423 and 425.98 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a waters XTERRA® MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=1.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.38 (dd, J=8.0, 7.8 Hz, 1H), 5.58-5.10 (m, 2H), 4.23 (br s, 1H), 3.62-3.39 (m, 1H), 2.58 (dt, J=13.3, 6.5 Hz, 1H), 2.46 (dd, J=13.3, 9.5 Hz, 1H), 1.73-1.51 (m, 1H), 1.47 (s, 9H), 0.85 (br s, 1H), 0.51 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[NH:33][C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH:38]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[N:33]([CH2:38][C:37]3[CH:40]=[CH:41][C:42]([Cl:43])=[C:35]([Cl:34])[CH:36]=3)[C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:24])([CH3:25])[O:18]1)[C:6]([NH:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2Cc1ccc(Cl)c(Cl)c1
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-2-{(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl}-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide (170 mg, 0.37 mmol) and 3,4-dichlorobenzaldehyde (129 mg, 0.74 mmol) and acetic acid (44 mg, 41 μL, 0.74 mmol) in 1,2-dichloroethane (1 mL) was stirred at room temperature for 30 minutes then treated with sodium triacetoxyborohydride (196 mg, 0.93 mmol). After 24 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with saturated aqueous sodium chloride (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic phase was collected, dried over MgSO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-{(1R,5S)-8-(3,4-dichlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide as a pale yellow oil which was used immediately in the next step; m/z for C32H50BCl2N3O4 expected 621.3. found 644.5 (M+Na(35Cl))+, 622.1 (M+H(35Cl))+,
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:14])=[C:6]([CH3:15])[C:5]=1[CH2:16][CH3:17])[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:37][Si:38]([CH3:43])([CH3:42])[CH2:39][CH2:40]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([C:4]1[C:12]([O:13][CH2:40][CH2:39][Si:38]([CH3:43])([CH3:42])[CH3:37])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:14])=[C:6]([CH3:15])[C:5]=1[CH2:16][CH3:17])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)CCO
Reactant: C=CCc1c(O)c2c(c(C)c1CC)COC2=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 6-allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one (199 mg, 0.857 mmol), PPh3 (337 mg, 1.286 mmol), and 2-trimethylsilylethanol in THF (3 mL) at 0° C. was added diisopropyl azodicarboxylate (259 mg, 1.286 mmol). The resulting yellow solution was allowed to warm to room temperature and stirred for one hour. The solvent was removed in vacuo and the crude material was dissolved in diethyl ether (3 mL). Hexanes (1.5 mL) were added. Triphenylphosphine oxide was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to provide the desired product (261 mg, 92%) as a clear oil. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.25 (m, 2H), 2.20 (s, 3H), 2.73 (q, J=7.8 Hz, 2H), 3.54 (m, 2H), 4.28 (m, 2H), 4.95 (d, J=17.1 Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.15 (s, 2H), 5.95 (m, 1H) ppm.
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[CH3:9].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([NH2:12])=[S:1])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(CC#N)cc1C
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CC(N)=S)cc1C

Procedure:
The 3,4-dimethylphenyl(thioacetamide) was prepared by passing a slow stream of hydrogen sulphide through a solution of 3,4-dimethylphenylacetonitrile (56.6 g.) in pyridine (60 ml.) and triethylamine (39.4 g.) during 12 hours. The reaction mixture was evaporated under reduced pressure and the residue was recrystallised from a mixture of benzene and light petroleum (b.p. 60°-80°) to give 3,4-dimethylphenyl (thioacetamide), m.p. 91°-94°.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(I)cc1
Yield: 90 %

Procedure:
2 mM of p-nitrophenol are reacted overnight with 2 mM of p-iodo benzoic acid chloride in the presence of 2 mM of triethylamine in 20 ml of THF. The solvent is evaporated and the residue is taken up in chloroform and washed with 1N HCl, then with water. The solution is dried over MgSO4. It is purified on a chromatography column (silica; eluant CHCl3 -hexane 85/15 v/v). Yield: 90%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.C([O-])=O.[NH4+]>[Pd].CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)(=[O:17])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:28][CH:29]=1
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a clear solution of methyl 3-[(4-methoxyphenethyl)-(3-nitrobenzenesulfonyl)-amino]-propionate in 5/1 methanol/ethyl acetate (30 mL) was added 10% Pd/C (300 mg) and ammonium formate (1.79 g, 28.4 mmol). After being stirred at room temperature for 24 h, the catalyst was filtered off through a pad of celite and the filtrate was concentrated. The residue was partitioned between methylene chloride (100 mL) and water (100 mL). Aqueous layer was extracted with another 100 mL of methylene chloride. Combined organic layer was washed with water (100 mL) and brine, dried over Na2SO4, filtered, and concentrated to give methyl 3-[(4-methoxyphenethyl)-(3-aminobenzenesulfonyl)-amino]-propionate (2.8 g, 7.1 mmol) as a yellow gummy product.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10]CC2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([C@@H:21]([N:23]2[CH2:27][C@H:26]3[CH:28]([NH2:31])[CH2:29][CH2:30][C@H:25]3[CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[C:1]1([C@H:7]([CH2:11][CH3:10])[C:12]([NH:31][C@H:28]2[C@H:26]3[C@H:25]([CH2:24][N:23]([C@H:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH3:22])[CH2:27]3)[CH2:30][CH2:29]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H]2CCC(N)[C@@H]2C1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CC[C@H](C(=O)N[C@@H]1CC[C@H]2CN([C@@H](C)c3ccccc3)C[C@H]21)c1ccccc1

Procedure:
The title compounds were prepared by substituting (S)-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS,6aR)-2-((S)-1-phenylethyl)octahydrocyclopenta[c]pyrrol-4-amine for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Examples 1 and 2.
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([SH:20])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.[C:22](=O)([O-])[O-].[K+].[K+].CI.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([S:20][CH3:22])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CC#N
Product: CSc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
A mixture of 3.43 g (10 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol, 20 ml of absolute acetonitrile and 1.38 g of (10 mmol) of potassium carbonate is treated with 0.93 ml (15 mmol) of methyl iodide and the mixture is stirred at 40° C. for 5 hours. The reaction mixture is then treated with saturated, aqueous sodium carbonate solution and extracted repeatedly using ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 3.4 g (95% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-methylthio-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of oil.
Reaction SMILES: N([O-])=O.[Na+].C[O:6][C:7](=[O:29])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)=[CH:14][C:13]=1N.[ClH:30]>O>[C:18]12([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][C:7]([OH:6])=[O:29])=[C:13]([Cl:30])[CH:14]=3)[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: COC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.00 g of sodium nitrite in 5 ml of water is added dropwise, whilst stirring, to a suspension of 5 g of 4-[4-(1-adamantyl)-2-amino-phenoxy)-butyric acid methyl ester in 10 ml of concentrated hydrochloric acid and 30 ml of water. After completion of the addition, the mixture is stirred for a further 3 hours at 0°C. The reaction solution is then filtered cold. The filtrate, kept at 0°C, is then added in portions to a solution of 5 g of freshly prepared copper-(I) chloride in 20 ml of concentrated hydrochloric acid at 0°C, whilst stirring. After completion of the addition, the temperature is allowed to rise to about 25°C and the mixture is then heated on a water bath until the evolution of nitrogen has ceased. It is then filtered, the residue is well rinsed with methylene chloride, and the filtrate is partitioned between 3 times 50 ml of methylene chloride and 50 ml of water. The organic phases are combined and evaporated in vacuo. The evaporation residue is dissolved in 100 ml of ethanol and 20 ml of 2 N sodium hydroxide solution and the mixture is left to stand for 24 hours at about 25°C. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 150 ml of 2 N hydrochloric acid and twice 50 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the evaporation residue on 100 g of silica gel, with ether as the migrating agent, and subsequent crystallisation from ethanol, gives 4-[4-(1-adamantyl)-2-chloro-phenoxy]-butyric acid of melting point 164°-166°C.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[C:17]4[C:20]5[C:25]([C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=6[C:16]4=[CH:15][C:14]=3[C:13]3[CH:12]=[C:11](B4OC(C)(C)C(C)(C)O4)[CH:10]=[CH:9][C:8]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N+:48]([O-:50])=[O:49].C([O-])([O-])=O.[Na+].[Na+].CCO>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>[N+:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:11]1[CH:10]=[CH:9][C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:19]3[CH:18]=[C:17]4[C:20]5[C:25]([C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=6[C:16]4=[CH:15][C:14]=3[C:13]=2[CH:12]=1)=[CH:24][CH:23]=[CH:22][CH:21]=5)([O-:50])=[O:49]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CC1(C)OB(c2ccc3c(c2)c2cc4c5ccccc5c5ccccc5c4cc2n3-c2ccccc2)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1-c1ccc2c(c1)c1cc3c4ccccc4c4ccccc4c3cc1n2-c1ccccc1
Temperature: 90 °C
Yield: 68.6 %

Procedure:
A mixture of 11.5 g (22.1 mmol) of 10-phenyl-13-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-10H-phenanthro[9,10-b]carbazole, 5.4 g (26.5 mmol) of 1-bromo-2-nitrobenzene, 0.44 g (0.4 mmol) of tetrakis(triphenylphosphine)palladium, 30 ml of 2M Na2CO3, 40 ml of EtOH and 80 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. overnight. After finishing the reaction, the mixture was allowed to cool to room temperature. The solution was extracted with 250 ml of ethyl acetate and 500 ml of water. The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (Hx-EA) to give product 7.8 g (69%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:14]([NH:21][CH:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc(CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-one (2.0 g, 11.4 mmol) (from Example 123) and benzylamine (1.33 g, 12.5 mmol) were dissolved in 1,2-dichloroethane (35 mL) and acetic acid (1.36 g, 22.6 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then cooled to 0° C. (ice-water) and sodium triacetoxyborohydride (3.14 g, 14.8 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Sat. NaHCO3 (aq) (30 mL) was added, and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane--30% ethyl acetate to give the product as a white solid.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:15].[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:16][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:15]
Reactant: CSC1C(=O)Nc2ccc([N+](=O)[O-])cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CSC1(Cl)C(=O)Nc2ccc([N+](=O)[O-])cc21

Procedure:
A solution of 3-methylthio-5-nitrooxindole (900 mg, 4 mmol) and N-chlorosuccinimide (600 mg, 4.5 mmol) in 50 ml of chloroform was stirred at room temperature for 1 hour and then evaporated to dryness in vacuo, yielding 3-chloro-3-methylthio-5-nitrooxindole. The residue was dissolved in 15 ml of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide powder (900 mg, 4.3 mmol) and boron trifluoride etherate (600 mg, 4.3 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for two hours, the reaction mixture was extracted with three 100-ml portions of chloroform. The chloroform layer was dried over anyhdrous magnesium sulfate, filtered and evaporated. The residue was recrystallized from 95 percent ethanol to give 5-nitroisatin (600 mg, 78%), mp 252°-254°
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.CN(C)C=O.[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(N(CC)CC)C>[F:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:34])[NH:2][C:3]2[CH:19]=[CH:18][C:17]3[C:8]4[NH:9][C:10](=[O:16])[C:11]5[N:12]([CH:13]=[CH:14][N:15]=5)[C:7]=4[CH2:6][C:5]=3[CH:4]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: O=C=Nc1cccc(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Yield: 21.5 %

Procedure:
The preparation is carried out as in Example 36 but from 1.5 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 30 ml of dimethylformamide, 0.97 g of triethylamine and 2.64 g of 3-fluorophenyl isocyanate. There is obtained 0.44 g of 8-[3-(3-fluoro-phenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-4-one in the form of a light brown solid melting above 260° C. (Analysis, % calculated C: 64.00, H: 3.76, F: 5.06, N: 18.66, O: 8.52, % found C: 64.1, H: 3.4, N: 18.6).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)[N:3]=1.O.[NH2:16][NH2:17]>O>[NH:16]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)[N:3]=1)[NH2:17]
Reactant: Clc1ccnc(-c2cccc(I)c2)n1
Reactant: NN
Solvent: O
Product: NNc1ccnc(-c2cccc(I)c2)n1

Procedure:
A mixture of 20.7 g of 4-chloro-2-(3-iodophenyl)pyrimidine, 140 ml of water and 80 ml of hydrazine hydrate was heated on a steam bath to produce solution, then refluxed 1/2 hour and allowed to cool overnight. The resulting crystals were collected, washed with methanol:water (1:1) and dried, giving 4-hydrazino-2-(3-iodophenyl)pyrimidine.