Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([CH3:30])=[CH:20][CH:21]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(C)cc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-p-tolyl-acrylic acid.
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:6]=2[S:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[C:19]([CH2:21][C:22]([NH2:24])=[S:23])#[N:20]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:7]2[C:8]3[N:24]=[C:22]([CH2:21][C:19]#[N:20])[S:23][C:2]=3[C:3]3[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=3[S:5][C:6]=2[CH:13]=1
Reactant: O=C1c2ccc(Cl)cc2Sc2ccccc2C1Br
Reactant: N#CCC(N)=S
Solvent: CCO
Product: N#CCc1nc2c(s1)-c1ccccc1Sc1cc(Cl)ccc1-2

Procedure:
To a solution of 11-bromo-7-chloro-11H-dibenzo[b,f]thiepin-10-one (3.75 mmoles) in absolute ethanol (19 ml), 2-cyanothioacetamide (5.63 mmoles) was added. The reaction mixture was heated under stirring and refluxing for 8 hours. Then the solvent was evaporated under reduced pressure and the remaining dry residue was dissolved in water and ethyl acetate. After extraction the organic layers were washed with a saturated aqueous NaHCO3 solution, water and a saturated aqueous sodium chloride solution. After purification by chromatography on a silica gel column a crystalline product was isolated.
Reaction SMILES: [CH3:1][C:2]1[N:23]([CH3:24])[C:5]2[CH:6]=[C:7]([C:20]([OH:22])=O)[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1.C[N:26](C)C=O>O1CCCC1>[CH3:1][C:2]1[N:23]([CH3:24])[C:5]2[CH:6]=[C:7]([C:20]([NH2:26])=[O:22])[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)N3
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2c3c(c(C(N)=O)cc2n1C)CCC(c1ccccc1)N3
Reaction time: 4 h
Yield: 71 %

Procedure:
To a suspension of 0.9 g (2.8 mmol) 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]quinoline-5-carboxylic acid in 10 ml tetrahydrofuran and 8 ml N,N-dimethylformamide were added 0.5 g (3.1 mmol) N,N′-carbonyldiimidazole. After 4 h at 60° C., the solution was cooled down and ammonia was bubbled through the flask for 4 h. The mixture was allowed to stand 60 h and then poured into 100 ml water. The precipitate was collected, washed with water and dried at 50° C. to yield 0.64 g (71%) of the title compound. m.p. 311-319° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][C:22]([C:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=5)=[CH:23][C:16]=34)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][C:22]([C:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=5)=[CH:23][C:16]=34)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4ccc5ncn(Cc6cccc(F)c6)c5c4)ccnc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(Cn2cnc3ccc(-c4ccnc5[nH]c(C6=CCNCC6)cc45)cc32)c1
Reaction time: 3 h

Procedure:
A solution of Example 14D (92.0 mg, 0.176 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (0.14 mL, 1.8 mmol) and the mixture was stirred for 3 hours and concentrated. The residue was dissolved in 2 mL of methanol and slowly treated with 3 mL 2M hydrogen chloride in ether. The suspension was stirred for 15 minutes and diluted with ether. The solids were filtered, washed with ether, treated with aqueous sodium bicarbonate, filtered, washed with water and concentrated to give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 2.23-2.29 (m, 2H), 2.92 (t, J=5.6 Hz, 2H), 3.38-3.46 (m, 1H), 5.64 (s, 2H), 6.33 (d, J=1.9 Hz, 1H), 6.53 (s, 1H), 7.11-7.17 (m, 3H), 7.19-7.25 (m, 1H), 7.40 (td, J=7.9, 6.1 Hz, 1H), 7.59 (dd, J=8.3, 1.6 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 8.22 (d, J=5.0 Hz, 1H), 8.54 (s, 1H), 11.81 (bs, 1H) MS (ESI+) m/z 424.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:22][CH3:23])[C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:12](Cl)=[O:13]>>[CH3:1][CH:2]([NH:6][C:12](=[O:13])[C:11]1[CH:10]=[C:9]([O:8][CH3:7])[C:17]([O:18][CH2:19][C:20]#[CH:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:3][CH2:4][CH3:5]
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: CCCC(C)N
Product: C#CCOc1c(OC)cc(C(=O)NC(C)CCC)cc1OC

Procedure:
According to the same method as that of Production Example 1, 1-methylbutylamine was used in place of 2,2-dimethylpropylamine, 3,5-dimethoxy-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1-methylbutyl)-3,5-dimethoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 56 of the present invention) represented by the formula:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[C:5]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:35])(=[N:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28])=[CH:23][CH:22]=1>>[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]1[C:5]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=[C:2]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:35])(=[N:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28])=[CH:23][CH:22]=2)[N:7]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: CC(=O)NCCNc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(NCCNC(C)=O)n2)cc1
Yield: 11 %

Procedure:
In the reaction of N-[2-(2-chloro-5-(2-thienyl)-pyrimidine-4-ylamino)ethyl]-acetamide (150 mg, 0.51 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxy-carbonyl)-S-methylsulfoximide (111 mg, 0.46 mmol) according to procedure 5a, the desired product is obtained in 11% yield (28 mg) after chromatographic purification (silica gel, dichloromethane/methanol (0%-10% methanol)).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]([NH:11][C@H:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:4](=[O:22])[N:3]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1.[H][H]>[Pd].CO>[CH3:38][C:2]1([CH3:1])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]([NH:11][C@H:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:10])[C:4](=[O:22])[N:3]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: CC(C)C[C@@H](C(=O)N[C@H](C)CC(=O)O)N1C(=O)N(Cc2ccc(C=Cc3ccccc3)cc2)C(C)(C)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)N[C@H](C)CC(=O)O)N1C(=O)N(Cc2ccc(CCc3ccccc3)cc2)C(C)(C)C1=O

Procedure:
The compound was prepared by catalytic hydrogenation of the styryl compound obtained in Example 1 (Pd/C, 1 bar hydrogen overpressure, methanol, room temperature).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][C:5]([CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[C:6]([CH3:8])[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1CN1CCOCC1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1CN1CCOCC1

Procedure:
The title compound was synthesized from 4-[(6-chloro-2-methylpyridin-3-yl)methyl]morpholine (90 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (130 mg, 0.42 mmol) according to the procedure described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:16]1[CH2:17][CH2:18][N:13]([CH2:11][CH:9]2[CH2:8][CH2:7][C:5]3[N:6]=[C:2]([NH2:1])[S:3][C:4]=3[CH2:10]2)[CH2:14][CH2:15]1
Reactant: Nc1nc2c(s1)CC(C(=O)N1CCN(c3ccccn3)CC1)CC2
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1nc2c(s1)CC(CN1CCN(c3ccccn3)CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (±)-1-[(2-amino-4,5,6,7-tetrahydro-6-benzothiazolyl)carbonyl]-4-(2-pyridinyl)-piperazine (2.8 g) (Example 6) in 200 ml of anhydrous tetrahydrofuran is treated with sodium borohydride (1.0 g) under nitrogen. The mixture is cooled in an ice bath and treated with boron trifluoride etherate (3.93 ml) dropwise. The reaction mixture is stirred at room temperature overnight, and quenched with 5 ml of glacial acetic acid. The mixture is evaporated in vacuo and the residue dissolved in 200 ml of a 10% solution of hydrochloric acid and refluxed for about 30 minutes. The solution is cooled in an ice bath and made basic with a concentrated solution of ammonium hydroxide and extracted with chloroform. The organic extract is dried (magnesium sulfate) and evaporated. The residue is triturated with 50 ml of warm diethyl ether and, after cooling to room temperature, is filtered. The title compound is obtained as a colorless solid; mp 177°-179° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]C)=O.[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C@@H:16]([NH:18][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](NC(=O)c1ccc[nH]1)c1ccccc1
Yield: 80.9 %

Procedure:
The title compound was prepared from methyl 1H-pyrrole-2-carboxylate (8.0 g, 0.06 mol) and (S)-1-phenylethanamine (24.7 ml, 0.19 mol) following the experimental procedure described in Preparation 44a. 10.4 g (75% yield) of the desired compound were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[N:7].[Na].[CH3:9][OH:10]>>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6](=[NH:7])[O:10][CH3:9]
Reactant: CO
Reactant: COCOCC#N
Agent: [Na]
Product: COCOCC(=N)OC

Procedure:
Obtained using the procedure described in section a of Example 2, starting with 286.8 g (2.84 moles) of methoxymethoxyacetonitrile [prepared according to D. J. Loder and W. M. Bruner, U.S. Pat. No. 2,398,757; C.A. 1946, 40, 3774] and 6.5 g (0.284 gram-atom) of sodium in 1430 ml of methanol. Reaction time: 2 days. Yld: 302.6 g (80%), b.p.15 62°-65° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9](F)[CH:8]=1>CS(C)=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[C:11]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=1
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Add pyrrolidine (0.97 g, 13.67 mmol) to a solution of 4-chloro-2-fluoro-1-nitrobenzene (2 g, 11.40 mmol) in 8 mL anhydrous DMSO under N2. Stir the reaction mixture at 80° C. for 1 h. Cool the mixture, pour into ice-H2O and extract with Et2O (3×30 mL). Wash the organic phase with water and brine, dry over MgSO4, filter, and concentrate. Chromatograph the residue on silica gel using hex/EtOAc 9:1 as eluent to afford 2.29 g (89%) of 1-(5-chloro-2-nitro-phenyl)-pyrrolidine as a yellow solid. Add tin chloride (10 g, 44.15 mmol) to a solution of 1-(5-chloro-2-nitrophenyl)pyrrolidine (2 g, 8.83 mmol) in 25 mL of EtOH under nitrogen. Heat the reaction mixture at 70° C. for 3 h. After cooling, pour the mixture into ice-water, basify (pH=9) with NH4OH, and extract with EtOAc (3×100 mL). Dry the organic phase over MgSO4, concentrate, and purify the residue by silica gel chromatography using hex/EtOAc 8:2 as eluent to obtain 1.56 g (88%) of 1-(2-amino-5-chlorophenyl)pyrrolidine as an oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:48][O:49][C:50](=[O:55])[C:51]([NH2:54])([CH3:53])[CH3:52]>CN(C=O)C>[CH3:48][O:49][C:50](=[O:55])[C:51]([NH:54][C:13]([C:4]1[CH:3]=[C:2]([Br:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12])=[O:15])([CH3:53])[CH3:52]
Reactant: O=C(O)c1cc(Br)c2ccccc2c1O
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1cc(Br)c2ccccc2c1O
Reaction time: 24 h
Yield: 70.2 %

Procedure:
To a solution of 1.5 g 4-bromo-1-hydroxy-2-naphthoic acid in 20 ml abs. DMF under inert atmosphere 0.84 g 1-hydroxybenzotriazole, 1.18 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.1 ml of N,N-diisopropylethylamine were added. After 15 minutes 0.86 g of 2-amino-2-methyl-propionic acid methyl ester hydrochloride, followed by 1.1 ml of N,N-diisopropylethylamine were added. After 24 h at room temperature and 2 h at 50° C. the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 1.44 g of 2-[(4-bromo-1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[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>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(Br)cccc1Br
Reactant: OB(O)c1ccccc1
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
Product: COC(=O)c1c(Br)cccc1-c1ccccc1

Procedure:
A mixture of the product from Example 114A (2.2 g, 7.5 mmol), phenylboronic acid (919 mg, 7.5 mmol), sodium carbonate (7.55 mL, 2 M aqueous solution, 15.1 mmol) tetrakis(triphenylphosphine)palladium(0) (261 mg, 0.23 mmol) and 50 mL of toluene were refluxed for 16 hours under nitrogen. The reaction was cooled and partitioned between 50 mL of water and 50 mL of ethyl acetate. The aqueous portion was separated and extracted with 2×25 mL of ethyl acetate and the combined organic extracts were washed with 2×25 mL of water and 1×25 mL of brine and dried over sodium sulfate. The organic solution was concentrated and the residue was purified via flash chromatography on a silica gel column (95:5 hexane:ethyl acetate) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.63 (s, 3H) 7.35-7.60 (m, 6H) 7.71-7.79 (m, 2H); MS (DCI+) m/z 308.0 [M+NH4]+.
Reaction SMILES: ON=[C:3]1[C:17]2[C:18]3[C:13]([CH:14]=[CH:15][N:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]2[C:4]1=[CH:5][CH:6]=[CH:7]2.[OH-:19].[Na+]>C(O)C.O>[CH:10]1[C:9]2[N:8]3[C:4]([C:3](=[O:19])[C:17]4[C:18]=2[C:13]([CH:14]=[CH:15][N:16]=4)=[CH:12][CH:11]=1)=[CH:5][CH:6]=[CH:7]3
Reactant: ON=c1c2nccc3cccc(c32)n2cccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1c2nccc3cccc(c32)n2cccc12

Procedure:
The 7-Imino-7H-indolizino[5,6,7-ij]isoquinoline (110 g.) and N sodium hydroxide solution ( ##SPC14## cc.) in ethanol (4.4 liters) and water (4.4 liters) are heated under reflux for 4 hours. After cooling, 7H-indolizino[5,6,7-ij]isoquinolin-7-one (108.1 g.) is obtained in the form of yellow needles melting at 264° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:15]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH:34]=3)(=[O:32])=[O:31])([CH:17]3[CH2:29][C:20]4[NH:21][C:22]5[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][C:27]=5[C:19]=4[CH2:18]3)[F:16])=[N:13][N:14]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl>C1COCC1>[Br:39][C:35]1[CH:34]=[C:33]([S:30]([C:15]([CH:17]2[CH2:29][C:20]3[NH:21][C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][C:27]=4[C:19]=3[CH2:18]2)([F:16])[C:12]2[O:11][C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=3)=[N:14][N:13]=2)(=[O:32])=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(-c2nnc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3cccc(Br)c3)o2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nnc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3cccc(Br)c3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 13 mg (0.02 mmol) of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,3,4]oxadiazol-2-yl}-benzoic acid methyl ester in a 1:1 mixture of 0.5 mL of THF and 0.5 mL of 1M aqueous LiOH was stirred at RT during one hour. Diluted aqueous HCl was added and the mixture extracted twice with dichloromethane. Drying of the combined organic phases over Na2SO4, filtration and evaporation of the solvent gave ca 13 mg (quantitative) of (RS, SR) 4-{5-[(3-bromo-benzenesulfonyl)-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,3,4]oxadiazol-2-yl}-benzoic acid as a yellow solid, MS: 632 (MH30 , 1Br).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:32])=[C:8]([CH:31]=1)[C:9](=[O:30])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)([OH:3])=[O:2].[Br:33]Br>C(O)(=O)C>[Br:33][C:6]1[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:31]=[C:8]2[C:7]=1[O:32][C:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=1)=[CH:10][C:9]2=[O:30]
Reactant: O=C(O)c1ccc(O)c(C(=O)C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c2oc(-c3ccc(OCc4ccc5ccccc5n4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
In a solution of 5'-carboxy-2'-hydroxy-4-(2-quinolinylmethoxy)chalcone (1 mmol) in 10 ml of glacial acetic acid, 0.06 ml of bromine was gradually added dropwise. The reaction mixture was stirred at room temperature for 3 hours, and the resulting yellow precipitate was collected and then washed with water. The precipitate was next dissolved in a mixed solvent which was consisted of 8 ml of ethanol and 15 ml of 6% potassium hydroxide. The resulting solution was stirred further for 4 hours. After the reaction mixture was acidified, the resulting precipitate was collected by filtration and then recrystallized from DMF, whereby the title compound represented by the following formula was obtained (yield: 25%). ##STR16##
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl[C:11]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12].O>[OH-].[Na+]>[CH3:17][O:16][CH2:15][CH2:14][O:13][C:11]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:12]
Reactant: COCCOC(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
To a solution of L-leucine (25 g, 0.19 mol) was dissolved in 2M NaOH (0.12 L) was slowly added 2-methoxyethyl chloroformate (30 g, 0.22 mol) and 1M NaOH at the same time under the ice-cooled condition. The mixture was stirred at room temperature for 18 hours, diluted into water (600 mL) and washed with ethyl ether (2×200 mL). The aqueous phase was cooled in an ice bath and acidified to pH 3 with 6M HCl. This mixture was extracted with ethyl acetate (EtOAc) (5×150 mL). The organic phase was dried over anhydrous MgSO4 and filtered, and the filtrate was concentrated in vacuo to yield N-((2-methoxyethoxy)carbonyl)-L-leucine (41 g, 92%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[N:7]([CH2:18][CH:17]=[CH2:16])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[Cl:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)Nc1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1cnccc1Cl
Temperature: 60 °C
Yield: 70.9 %

Procedure:
A mixture of (4-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (6.78 g, 29.7 mmol), allyl bromide (5.1 g, 40.8 mmol) and cesium carbonate (20.1 g, 61.8 mmol) in DMF (200 mL) is heated at 60° C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography eluting with 0-40% EtOAc in heptane to afford allyl-(4-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (5.66 g, 71%). MS: 269 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.42(d, 1H), 7.40 (d, 1H), 5.80-5.98 (m, 1H), 4.35-4.51 (m, 1H), 3.90-4.07 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH2:19]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:26]([C:25]3[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=3[O:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1(b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[C@H:22]([CH3:23])[CH2:21][CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@H:17]([OH:18])[C@@H:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][C@H:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@H]2O[C@H]2CN1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CC[C@H](N=[N+]=[N-])[C@@H](O)CN1C(=O)OCc1ccccc1
Yield: 88.9 %

Procedure:
Sodium azide (0.139 g, 2.14 mmol) was added to a solution of (1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14 mmol) in MeOH (1.5 ml) and H2O (0.15 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexanes) to yield the title compound (0.192 g, 89%): 7.39–7.30 (m, 5H), 5.15 (2H, s), 4.10–3.67 (m, 2H), 3.10 (1H, d), 1.85–1.53 (m, 4H), 1.09 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=305.2.