Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:10](=[O:18])[CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[CH2:13]([CH:12]1[C:11]([CH:10]=[O:18])=[CH:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC=CC=O
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCC1Oc2ccccc2C=C1C=O
Yield: 48 %

Procedure:
A mixture of 22.0 g (0.18 mol) of salicylaldehyde, 25.0 g (0.198 mol) of 2-octenal and 24.8 g (0.18 mol) of potassium carbonate in 200 ml of dioxane, maintained under an inert atmosphere, is heated at reflux for 2.5 h. The reaction mixture is subsequently brought to room temperature (20-25° C.) and then diluted by addition of 1.5 litres of water. The formation of an oil is observed, which oil is extracted with methylene chloride. The organic phase is dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The title compound is thus obtained in a form of an orange oil, which oil is distilled under reduced pressure (B.p. (0.44 mm Hg): 132-140° C.). 20 g of the title product are obtained by distillation (48% yield).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[C@@H:21]2[O:25][C@H:24]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])[C@@H:23]([OH:31])[C@H:22]2[OH:32])=[C:14]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:13]=1>>[CH:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][N:18]3[C@@H:21]3[O:25][C@H:24]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])[C@@H:23]([OH:31])[C@H:22]3[OH:32])=[C:14]([NH:33][CH2:34][CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C=NC1CCCCC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NC4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The compound was prepared from cyclohexylisocyanate and (2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (Preparation 11) according to the procedure used in Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:36]1C=CC(OC)=C(S(Cl)(=O)=O)C=1>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 521.18 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH2:17][CH2:16]3)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2,4-dichloro-5-nitropyrimidine (5.0 g, 25.8 mmol) in dioxane (35 mL) was added a solution of 5-aminoindane (3.43 g, 25.8 mmol) in dioxane (9 mL) and diisopropylethyl amine (4.5 mL, 25.8 mmol). The mixture was stirred at 25° C. for 1 hr and then concentrated to a residue to provide crude (2-chloro-5-nitro-pyrimidin-4-yl)-indan-5-yl-amine, (1).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(Cl)Cl>[CH3:30][NH:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[N:24][CH:25]=1
Reactant: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: CNC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Oc2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nc1
Temperature: 100 °C

Procedure:
A mixture of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol (Example 47, 20 mg, 0.066 mmol), 6-chloro-N-methylnicotinamide (Example 71A, 11 mg, 0.066 mmol) and K2CO3 (27 mg, 0.20 mmol) in N,N-dimethylformamide (0.25 mL) was heated to 100° C. for 1 hour, cooled, diluted with CH2Cl2, filtered, and concentrated. The residue was purified by HPLC as described in Example 66. The product was further purified by chromatography on silica gel eluting with a gradient of 2 to 10% (9:1 methanol:ammonium hydroxide) in CH2Cl2 to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.44-1.53 (m, 2H), 1.59-1.67 (m, 4H), 1.94-2.10 (m, 1H), 2.24-2.34 (m, 1H), 2.39-2.57 (m, 4H), 2.95-3.06 (m, 1H), 3.01 (d, J=4.7 Hz, 3H), 3.43 (t, J=9.3 Hz, 1H), 3.48-3.60 (m, 1H), 3.70-3.89 (m, 2H), 6.09-6.18 (m, 1H), 6.92 (dd, J=8.5, 0.7 Hz, 1H), 7.07 (dd, J=8.5, 2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 8.12 (dd, J=8.6, 2.5 Hz, 1H), 8.53 (dd, J=2.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 438 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([OH:27])=[O:26])=[CH:33][CH:34]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Yield: 4.4 %

Procedure:
Methyl 2-[(4-{3-[4-(benzyloxy)phenoxy]propyl}phenoxy)methyl]benzoate (0.047 g, 0.097 mmol) was dissolved in a mixture of THF/water (7/1, 2 ml) and lithium hydroxide (9.3 mg, 0.39 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation. The crude product was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 2 mg of 2-[(4{3-[4-(benzyloxy)phenoxy]propyl}phenoxy)methyl]-benzoic acid (yield 4.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.O=[CH:12][C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[N:9]=[C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)[CH:12]=[N:10]2
Reactant: COc1ccc(N)c(N)c1
Reactant: COC(=O)c1ccc(C(=O)C=O)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3n2)cc1

Procedure:
To a solution of methyl 4-acetylbenzoate (1.00 g, 5.61 mmol) in DMSO (5 mL) was slowly added 40% HBr (1.5 mL) at 20° C. under stirring. The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (10 mL) and the resulting mixture was extracted with DCM (10 mL×3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give methyl 4-(2-oxoacetyl)benzoate (150 mg), which was taken forward without further purification. To a solution of 4-methoxybenzene-1,2-diamine (107 mg, 0.78 mmol) in 5 mL of acetic acid was added the crude methyl 4-(2-oxoacetyl)benzoate (150 mg). The mixture was refluxed for 2.5 hours. The solvent was removed in vacuo. The crude product was purified by prep-TLC (PE/EA: 1/1) to separate the desired methyl 4-(6-methoxyquinoxalin-2-yl)benzoate (more polar) from the undesired methyl 4-(7-methoxyquinoxalin-2-yl)benzoate. The two structures were confirmed by HMBC spectra.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=[CH:10][CH:11]=1>[Ni].O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cccc(OCCCBr)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc(OCCCBr)c1

Procedure:
1 g of Raney nickel is added to a solution of 4 g of 3-(3-bromopropoxy)-nitrobenzene in 40 ml of tetrahydrofuran and the whole is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. After concentration of the filtrate by evaporation, 3-(3-bromopropoxy)-aniline is obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[O:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([C:14]3([OH:17])[CH2:15][CH2:16][O:12][CH2:13]3)[O:9][C:8]=12
Reactant: COc1nccc2ccoc12
Reactant: O=C1CCOC1
Product: COc1nccc2cc(C3(O)CCOC3)oc12
Yield: 50.7 %

Procedure:
Starting from 7-methoxyfuro[2,3-c]pyridine (2.5 g) and dihydrofuran-3-one (1.7 g). Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a brown oil (2 g).
Reaction SMILES: C([O:5][C:6](=[O:42])[CH:7]([NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[C:35]1([CH2:34][C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:18]([NH:17][C@H:7]([C:6]([OH:42])=[O:5])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:19])=[CH:21][CH:22]=3)=[CH:27][CH:28]=2)=[O:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)Cc3ccccc3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@H](NC(=O)c1ccc(-c2ccc(NC(=O)Cc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
2-[(4′-Phenylacetylamino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (45 mg) was dissolved in dichloroethane (3 mL) and added to TFA (1 mL). The mixture was stirred at room temperature for 3 hrs. Reaction was complete as determined by TLC. Solvent was removed and the resulting solid was dried under vacuum overnight. N-({4′ [(phenylacetyl)amino]-1,1′-biphenyl-4-yl}carbonyl)-L-glutamic acid was obtained in 84.2% yield (30.3 mg). MS (ESI) m/z 461.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]([CH3:29])[CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][CH2:19][N:18]([CH3:29])[CH3:17])=[CH:27][CH:26]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN(C)CCSc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCSc1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.21 g, 0.76 mmol) and 4-(2-dimethylamino-ethylsulfanyl)-phenylamine (0.15 g, 0.76 mmol) were stirred in N,N-dimethylformamide (5 mL) and triethylamine (0.3 mL) at 60-70° C. for 5 minutes and then at room temperature for 10 minutes. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-{[(4-{[2-(dimethylamino)ethyl]thio}phenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.22 mg, 65%) as a golden powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([CH2:12][O:13][CH3:14])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: COCc1ccc(C)c(NCC=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COCc1ccc(C)c(N(CC=O)C(=O)CCl)c1
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-methoxymethylanilino)acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-methoxymethylanilino)-acetaldehyde.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>O>[C:30]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:32])[CH3:31]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)cc1C(=O)O
Reaction time: 8 h

Procedure:
A mixture of 26.2 g. (0.069 mole) of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole and 204 g. of acetic anhydride was stirred at 75° for 4 hours, cooled, treated with 34 g. of water, stirred for several hours until a solution formed, and allowed to stand overnight. The solid which separated was collected, washed with acetic acid and petroleum ether, and dried to provide 26.7 g. (91%) of crystals, m.p. 194°-196°.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33])[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH:4]1[C:3](=[O:2])[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:11][C:6]=2[CH2:5]1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccccc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccccc1C1Cc2cnc(Nc3ccccc3)nc2N(c2ccccc2)C1=O
Temperature: 110 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(2-dimethoxy-phenyl propionic acid methyl ester (181.8 mg, 0.40 mmol) (from Example 7b supra) was added 5% concentrated sulfuric acid in glacial acetic acid (3 mL) in one portion. The reaction mixture was heated at 110° C. for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was crystallized from ethyl acetate-hexanes to give 6-(2-methoxy-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid. (Yield 119.4 mg, 67.2%).
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[C:1]12([C:11]([O:13][CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC(=O)C12CC3CC(CC(C3)C1)C2)C(C)=O
Temperature: 80 °C
Reaction time: 10 h

Procedure:
200 mmol of 1-adamantanecarboxylic acid are added to 100 mmol of sodium carbonate placed in 160 ml of DMF. The mixture is heated to 80° C. and then 200 mmol of ethyl 2-chloroacetoacetate in solution in 40 ml of DMF are added. The temperature and the stirring are maintained for three hours and then the mixture is left for 10 hours at room temperature. After evaporation of the DMF, the residue is taken up in 300 ml of water and 300 ml of ether. After extraction, drying and evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:25][C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:31]1([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C1CCCCC1
Reactant: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCN)cc1)Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC2CCCCC2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
The compound (173.5 mg) obtained in Example 102-4 was dissolved in anhydrous methanol (7.0 ml). Then, the solution was added with cyclohexanone (0.083 ml) and sodium cyanoborohydride (75.4 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16.5 hours. After the reaction, the solvent was distilled off. Subsequently, the residue was added with a 1 mol/l sodium hydroxide aqueous solution (7.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (161.6 mg) of the subject compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](Cl)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][S:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)(=[O:14])=[O:13])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3ccccc23)CC1
Temperature: 25 °C

Procedure:
4-Fluoro-naphthalene-1-sulfonyl chloride 27 (10.0 g, 40.9 mmol) was dissolved in THF (100 mL) and stirred at room temperature. 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (8.19 g, 40.9 mmol) and triethylamine (4.14 g, 5.75 mL, 40.9 mmol) were added and the reaction was stirred overnight at room temperature. The solvent was removed in vacuo. Dichloromethane (250 mL) was added and the solution was charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over MgSO4. Filtration and concentration in vacuo afforded 28 as a yellow foam. Wt.: 15.1 g (90%). 1H NMR (300 MHz, CDCl3) δ 8.62 (d, 1H), 8.26 (m, 2H), 7.69 (m, 2H), 7.20 (m, 1H), 4.92 (d, 1H), 3.82 (m, 2H), 3.26 (m, 1H), 2.70 (m, 2H), 1.61 (m, 2H), 1.40 (s, 9H), 1.24 (m, 2H); LC/MS m/z 409 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([CH2:30][CH:31]3[CH2:35][CH2:34][N:33]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[C:32]3=[O:42])=[C:25]([Cl:43])[CH:24]=2)=[CH:19][CH:18]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:36]1([N:33]2[CH2:34][CH2:35][CH:31]([CH2:30][C:26]3[C:27]([Cl:29])=[CH:28][C:23]([C:20]4[CH:21]=[CH:22][C:17]([C:15]([N:11]5[CH2:10][CH:9]6[CH2:14][CH:12]5[CH2:13][NH:8]6)=[O:16])=[CH:18][CH:19]=4)=[CH:24][C:25]=3[Cl:43])[C:32]2=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2C(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CC2CC1CN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Dissolve chiral 5-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.119 g, 0.19 mmol) in dichloromethane (3 mL), treat with trifluoroacetic acid (1 mL) and stir for 1 hour at room temperature. Remove the solvent under vacuum, dissolve the residue in ethyl acetate and wash with saturated aqueous sodium bicarbonate then water. Dry the organic layer with sodium sulfate, concentrate under vacuum and purify the crude product by silica gel chromatography using a gradient of 0 to 10% methanol in dichloromethane to afford 100 mg (100%) of the title compound: MS (m/z): 526 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[C:16]1[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][C:15]1=[O:23])[CH2:7][CH2:6]2
Reactant: CN(C)c1ccc2c(c1)CCC2=O
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CN(C)c1ccc2c(c1)CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 4.2 %

Procedure:
A mixture of 0.5 g 5-dimethylamino-1-indanone, 1.1 g oxindole and 2.5 ml piperidine in 4 ml dimethylforamide was heated in a sealed tube at 130° C. for 12 hours to yield a reddish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. Chromatography afforded 35 mg of 3-(5-dimethylamino-indan-1-ylidene)-1,3-dihydroindol-2-one as a brown solid.