Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH2:27][C:28]1[CH:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][N:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][N:29]=1)[C:34]([NH:13][C:10]1[N:9]2[CH2:14][CH2:15][N:16]=[C:8]2[C:7]2[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[C:3]([O:2][CH3:1])[C:12]=2[N:11]=1)=[O:35]
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1cc(C(=O)O)ccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1ccnc(N)c1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (100 mg, 0.28 mol) was dissolved in DMF (3 mL), and 2-aminopyridine-4-carboxylic acid (38 mg, 0.28 mmol) was added. PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (0.15 mL, 0.83 mmol) were subsequently added, and the mixture was stirred at rt overnight. The mixture was purified by HPLC to give the title compound (50 mg, 37%). LC MS RT=1.02 min, MH+=480.3. 1H NMR (DMSO-d6) δ: 13.25 (1H, br s), 10.15 (1H, br s), 8.42 (1H, br s), 8.08 (1H, s), 8.06 (1H, d), 7.43 (1H, d), 7.75 (1H, s), 7.50 (1H, d), 7.38 (1H, dd), 4.50 (2H, dd), 4.35 (2H, br t), 4.27 (2H, dd), 4.01 (3H, s), 3.99 (2H, br s), 3.66 (2H, t), 3.50 (2H, d), 3.31 (2H, br t), 3.13 (2H, m), 2.25 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([Cl:29])=[O:19])=[CH:21][CH:22]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Yield: 173.1 %

Procedure:
In a suspension of 1.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] benzoic acid in 10 ml of benzene, 0.44 g of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred under reflux with heat for 2.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1.81 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] benzoic acid chloride as pale yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[N:15]([CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:23]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[N:15]([CH:16]=3)[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:4][CH:3]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: C1COCCN1
Reactant: Brc1ccc(-c2cc3ccccn3c2)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: c1ccn2cc(-c3ccc(N4CCOCC4)cc3)cc2c1
Yield: 24.4 %

Procedure:
To 2-(4-bromo-phenyl)-indolizine (1.2 g, 4.42 mmol) in toluene (8 mL) was added cesium carbonate (4.3 g, 13.24 mmol) and morpholine (1.15 mL, 13.24 mmol). To this was added a mixture of bis-(triphenylphosphine)-palladium (II) chloride (120 mg) and 2-dicyclohexylphosphino-2′-(N,N′-dimethylamino)biphenyl (150 mg) in toluene (10 mL). The reaction mixture was degassed for 15 min and then refluxed for 16 h under an atmosphere of argon. The cooled reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane. The organic layer was washed with water and brine solution (×2), dried over sodium sulfate, filtered and concentrated. The crude compound was purified by column chromatography over silica gel (60-120 mesh) with 80% chloroform/petroleum ether to afford 2-(4-morpholin-4-yl-phenyl)-indolizine (300 mg, 24%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[N:39]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[N:42]([CH3:43])[C:41]5[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=5[N:39]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2nc3ccccc3n2C)C[C@H](C)N1
Product: C[C@@H]1CN(c2nc3ccccc3n2C)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 42 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-1-methyl-1H-benzimidazole.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C:12]2[C@:7]1([CH3:24])[CH2:8][CH2:9][C@H:10](OC(N1C=CN=C1)=S)[CH:11]=2)([CH3:4])([CH3:3])[CH3:2].C([SnH](CCCC)CCCC)CCC.C(B(CC)CC)C>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([O:5][C@@H:6]1[C@:7]2([CH3:24])[C:12](=[CH:11][CH2:10][CH2:9][CH2:8]2)[CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1CCCC2=C[C@@H](OC(=S)n3ccnc3)CC[C@@]21C
Agent: CCB(CC)CC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)O[C@H]1CCCC2=CCCC[C@@]21C
Temperature: 120 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
To a stirred solution of 9.95 g (28.5 mMol) imidazole-1-carbothioic acid(2S, 4aS, 5S)-O-(5-tert-butoxy-4a-methyl-2,3,4,4a,5,6,7,8-octahydro-naphtalen -2-yl)ester in 285 ml toluene kept under argon atmosphere were added 75.7 ml (285 mMol) of tributyltinhydride and 75.7 ml of a one molar solution of triethylborane in tetrahydrofuran. The reaction mixture was heated to 120° C. for 4 hours and additional 20 ml of tributyltinhydride as well as 20 ml of triethylborane solution (one molar in tetrahydrofuran) were added. The reaction mixture was kept at 120° C. for 3 days, cooled to room temperature and evaporated in vacuo. The residue was chromatographed twice over 900 g silica gel with toluene/hexane 1/1 to yield 4.3 g of pure (4S,4aS)-4-tert-Butoxy-4a-methyl-1,2,3,4,4a,5,6,7-octahydro-naphtalene (liquid).
Reaction SMILES: [Cl-].[NH4+].O.[I:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]>C(O)C.[Fe]>[I:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COCCOc1ccc(N)cc1I
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A suspension of iron (3.89 g, 69.7 mmol), ammonium chloride (5.0 g, 93.5 mmol), in 100 mL of ethanol and 28 mL of water was heated to reflux. 2-Iodo-1-(2-methoxyethoxy)-4-nitrobenzene (7.5 g, 23.2 mmol) was added and the reaction was heated at reflux for 3 hours. The mixture was cooled to room temperature and filtered through Celite, washed with ethanol. The filtrate was concentrated in vacuo until a precipitate appeared. The precipitate was removed by filtration through Magnesol and the filtrate was concentrated in vacuo to provide 4.0 g of [3-iodo-4-(2-methoxyethoxy)phenyl]amine as an oil; 1H NMR (300 MHz, DMSO-d6) δ 3.33 (s, 3H), 3.62 (t, 2H), 3.95 (t, 2H), 5.01 (d, 2H), 6.55 (d, 1H), 6.73 (d, 1H), 7.03 (s, 1H); MS (ES) m/z294.0 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[N:20][C:19]4[CH:31]=[CH:32][CH:33]=[N:34][C:18]3=4)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[C:21]([CH2:24][C:25]4[CH:26]=[N+:27]([O-:43])[CH:28]=[CH:29][CH:30]=4)=[N:20][C:19]4[CH:31]=[CH:32][CH:33]=[N:34][C:18]3=4)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1c(Cc2cccnc2)nc2cccnc2n1-c1cccc(/C=C/c2cc(Cl)cc(Cl)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2ccc[n+]([O-])c2)nc2cccnc2n1-c1cccc(/C=C/c2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of 4-[3-[(E)-2-(3,5-dichlorophenyl)vinyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (255 mg) in dichloromethane (10 ml) was added m-chloroperbenzoic acid (181 mg). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate and extracted with chloroform. The organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with diisopropyl ether to give 4-[3-[(E)-2-(3,5-dichlorophenyl) vinyl]phenyl]-2-[(1-oxido-3-pyridyl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (167 mg).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5](O)[CH:4]=1)#[N:2].[Li+].[BH4-].Cl.C1C[O:20]CC1>>[OH:8][CH2:7][C:6]1[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[C:4]([OH:20])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)cc1O
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Product: N#Cc1ccc(CO)cc1O
Temperature: 25 °C

Procedure:
Methyl 4-cyano-2-hydroxybenzoate (0.50 g, 2.82 mmol) was dissolved in dry THF (30 mL), treated with LiBH4 (2.0 M solution in THF) (5.64 mL, 11.28 mmol), and heated at reflux for 18 hr. The reaction mixture was cooled to room temperature, poured into 1N HCl solution and extracted with EtOAc (2×). Organics combined and dried (MgSO4), filtered and concentrated to dryness to give the title compound which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7](=[NH:11])OCC.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([NH:18][C:7]([C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[OH:1])=[NH:11])[CH3:17]
Reactant: CCOC(=N)c1sc2ccccc2c1O
Reactant: CCN
Product: CCNC(=N)c1sc2ccccc2c1O
Yield: 67 %

Procedure:
3 g of ethyl 3-hydroxy-benzo[b]thiophene-2-carboximidate (Example 2) are heated under reflux for 10 hours in 20 g of 33% aqueous ethylamine solution. The residue obtained after evaporation is recrystallized from an ethyl acetate/isopropanol solution and yields 2 g of the product.
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]Cl)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCOCC>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[C:14]#[N:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCN1CCC(Cc2ccccc2)CC1
Reactant: N#CCc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1cccc2ccccc12

Procedure:
2 g of sodium amide are added in small portions to a solution of naphth-1-ylacetonitrile in 150 ml of anhydrous ether and the mixture is refluxed for 5 hours. 11.8 g of 2-(4-benzylpiperidino)chloroethane are then added and the mixture is refluxed again for 3.5 hours. 200 ml of water are added and the organic phase is decanted and extracted with 300 ml of 10% hydrochloric acid. The aqueous phase is washed with ether, neutralized with 30% sodium hydroxide and extracted with ether. The organic phase is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate and the solvent is then evaporated off to give 16.4 g of the expected product.
Reaction SMILES: [CH2:1]([N:3]([CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH2:4][CH3:5])[CH3:2].[OH-].[Na+]>CO>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:23]([NH:22][CH2:21][CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]([OH:9])=[O:8])=[CH:14][CH:15]=2)=[O:36])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)N(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
Ethyl 2-(N,N-diethylamino)-3-[4-[2-(4-phenylbenzoylamino)ethoxy]phenyl]-propionate, which is the product of Example 189, is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:12]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:12])=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Methyl 3-amino-2-pyrazine-carboxylate (10 g, 65.3 mmol) was dissolved in glacial acetic acid (50 mL) by warming to approximately 45° C. To the warm solution was added bromine (3.7 mL) in acetic acid (5 mL) dropwise and the resulting mixture was stirred at room temperature for 20 minutes. The solution was diluted with water (300 mL) and then stirred at room temperature for 30 minutes, which resulted in a precipitate. The precipitate was then filtered, washed with water and dried to afford methyl 3-amino-6-bromo-2-pyrazine-carboxylate as a yellow solid (14.2 g, 94%). 1H NMR (300 MHz, CDCl3) δ3.99 (s, 3H), 8.30 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 53.02, 123.49, 124.85, 150.24, 154.70, 166.04.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20](=O)[CH2:21][CH2:22][C:23](=O)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:1]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]3[CH3:19])[N:7]=2)[CH:17]=1
Reactant: Nc1cccc(Nc2cc(Cl)ccc2C(=O)O)n1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(C)n1-c1cccc(Nc2cc(Cl)ccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A slurry of 2-(6-amino-pyridin-2-ylamino)-4-chlorobenzoic acid (2.4 g) and 2,5-hexanedione (1.04 g) and p-toluenesulfonic acid (0.15 g) was heated at reflux in a Dean-Stark trap for 24 h. The resulting mixture was cooled to RT and filtered, then stirred with H2O (50 mL) overnight, filtered, and dried to yield 4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-benzoic acid (2.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([S:8][C:9]1[CH:14]=[C:13]([NH2:15])[C:12]([F:16])=[CH:11][C:10]=1[Cl:17])[CH2:5][CH2:6]Br.C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1([S:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([F:16])=[CH:11][C:10]=2[Cl:17])[CH2:6][CH2:5]1)=[O:18]
Reactant: COC(=O)C(CCBr)Sc1cc(N)c(F)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: COC(=O)C1(Sc2cc(N)c(F)cc2Cl)CC1
Yield: 175.9 %

Procedure:
A mixture of 12.5 g of 2-(5-amino-2-chloro-4-fluorophenylthio)-4-bromobutyric acid methyl ester, 30.4 g of potassium carbonate and 1.7 g of tetrabutylammonium hydrogen sulfate in 38 ml of toluene is maintained at +80° C. for 40 hours. The solid portions of the reaction mixture are then filtered off and washed with acetone. Evaporation of the solvent yields 17 g of 1-(5-amino-2-chloro-4-fluorophenylthio)-cyclopropanecarboxylic acid methyl ester having a melting point of from +119° to +124° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[C:17]([Cl:22])=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:22][C:17]1[C:16]([N:4]2[CH2:5][CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:2]([CH3:1])[C:3]2=[O:14])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: Clc1ncccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1C(=O)N(c2cccnc2Cl)CC1C(=O)OC(C)(C)C
Yield: 57.1 %

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (650 mg, 3.25 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 3-bromo-2-chloropyridine (625 mg, 3.25 mmol) in 1,4-dioxane (30 ml) was added cesium carbonate (4231 mg, 12.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (149 mg, 0.162 mmol) and Xantphos™ (141 mg, 0.243 mmol) and the reaction stirred at reflux overnight. The reaction mixture was allowed to cool and solvent was removed under vacuum and the residue partitioned between ethyl acetate and water. The organic layer was separated and washed with saturated sodium hydrogen carbonate solution, water and brine and separated by hydrophobic frit. The organic solution was reduced under vacuum and the residue purified by SP4 automated silica gel chromatography eluting with 10-80% ethyl acetate in iso-hexane to give 1,1-dimethylethyl 1-(2-chloro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (579 mg, 51.5% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: COc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1
Product: COc1cccc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 1-(m-methoxyphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(m-methoxyphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.CN(C)C=O>[C:6]1([CH3:5])[CH:11]=[CH:10][C:9]([S:12]([CH2:2][C:3]#[N:4])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: N#CCBr
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
3.37 g (28 mmol) of bromoacetonitrile and 640 mg (2.8 mmol) of benzyltriethylammonium chloride are added to a solution of 5 g (28 mmol) of sodium 4-methyl-benzenesulfinate in 50 ml of toluene and 50 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 24 h. The heterogeneous mixture is filtered. The filtrate is evaporated and then purified on silica gel (heptane then heptane/ethyl acetate, 60/40 v/v). The product is triturated in heptane then filtered and dried. 2.95 g of (toluene-4-sulfonyl)-acetonitrile is obtained in the form of a pale yellow powder. (Yield=54%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH:8]=1>C(O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:8]1
Reactant: C1=C(c2cnccn2)C2CCN1CC2
Solvent: CCO
Product: c1cnc(C2CN3CCC2CC3)cn1
Yield: 72.7 %

Procedure:
A solution of 3-(2-pyrazinyl)-1-azabicyclo [2.2.2]-oct-2-ene (75 mg, 0.4 mmol), in ethanol (20 ml), was hydrogenated over 10% pd/C (75 mg) in a Parr apparatus. After 1.5 h the catalyst was removed by filtration through hyflo and the solvent removed under reduced pressure. Chromatography of the residue through alumina eluting with dichloromethane/methanol (95:5) gave 3-(2-pyrazinyl)-1-azabicyclo [2.2.2]octane (55 mg) as a pale yellow oil. The hydrochloride salt was prepared, m.p. 203°-205° C. (isopropyl alcohol/ether); (Found C, 55.23; H, 7.15; N, 17.86 C11H15N3. HCl. 0.75 H2O requires C, 55.23; H, 7.32: N, 17.57%); m/e 189 (M+ for free base); δ (360 MHz, D2O) 1.70-1.85 (2H, m, CH2); 2.10-2.30 (2H, m, CH2); 2.40-2.48 (1H, m, CH-bridgehead); 3.28-4.04 (7H, m, 3×CH2 and CH); 8.52 (1H, m, pyrazine-H); 8.63 (2H, m, pyrazine-H).
Reaction SMILES: [CH:1]1([CH:9]2[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH:12]([CH:21]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:11]=[N:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1CCCCC1.[O-2].[Al+3].[Rh+3].[O-2].[O-2]>[CH:1]1([CH:9]([NH2:10])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([CH:21]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[NH2:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCC(C2CCCCCCC2)N=NC(C2CCCCCCC2)CC=CCC1
Agent: [Rh+3]
Agent: [Al+3]
Agent: [O-2]
Solvent: C1CCCCC1
Product: NC(CCCCCCCCC(N)C1CCCCCCC1)C1CCCCCCC1
Reaction time: 6 h

Procedure:
2.5 g (6.5 mmols) of 3,12-dicyclooctyl-1,2-diaza-1,5,9-cyclododecatriene are hydrogenated, in 100 ml of cyclohexane in a stirred autoclave and with the addition of 0.6 g of rhodium-aluminum oxide (5% by weight of rhodium), first at room temperature for 90 minutes and then at 210°-220° C for 6 hours. After filtering off the catalyst and stripping off the solvent on a rotary evaporator, 2.4 g of crude 1,10-dicyclooctyl-1,10-diaminodecane are produced.
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][S:5]([N:8]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)(=[O:7])=[O:6].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][C:32](=O)[O:33]C1C=CC=CC=1>CS(C)=O.O>[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][C:32]([N:13]1[CH2:12][CH2:11][C:10]2([C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:8]([S:5]([CH3:4])(=[O:6])=[O:7])[CH2:9]2)[CH2:15][CH2:14]1)=[O:33]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccccc1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)N1CC2(CCN(C(=O)Nc3nc4ccccc4s3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
10 M aqueous NaOH solution (75 uL) was added to a solution of 1-methylsulfonylspiro[indoline-3,4′-piperidine]hydrochloride 2-1 (225 mg, 0.74 mmol) in DMSO (2.5 mL). Phenyl N-(2-benzothiazolyl)carbamate 2-2 (200 mg, 0.74 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 20 h. The mixtrue was diluted with water and extracted with EtOAc. The organic extract was washed with dil. NaOH and brine, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 200 (279 mg, 85%) as a colorless amorphous solid.