Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:20][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[NH2:16][C:17]1[CH:18]=[C:19]([CH2:20][C@H:21]([NH:22][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:23]([OH:25])=[O:24])[CH:26]=[CH:27][C:28]=1[O:29][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1
Reactant: Nc1cc(C[C@H](N)C(=O)O)ccc1O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: Nc1cc(C[C@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)ccc1Oc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-amino-4-hydroxy-L-phenylalanine and crude product is separated by flash chromatography on SiO2 to provide the title compound in good yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>[Pt]=O.C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: O=C1CCCCC(CCc2ccccn2)N1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C1CCCCC(CCC2CCCCN2)N1
Yield: 93.2 %

Procedure:
Example 296 A) A sample of the Hexahydro-7-[2-(2-pyridyl) ethyl]-1H-azepin-2-one product of Example 290b (2.4 g, 11 mmol), platinum oxide (500 mg) and glacial acetic acid (30 mL) were shaken on a Parr hydrogenator at 55 psi of hydrogen overnight. The contents were filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and adjusted to pH 9 with 2.5N NaOH. The aqueous solution was extracted with CH2Cl2 and the organic layer was dried over MgSO4 and concentrated in vacuo leaving hexahydro-7-[2-(2-piperidyl)ethyl]-1H-azepin-2-one as a white solid (2.3 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[F:44]>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@H:25]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=3[F:44])[OH:26])=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)cc1F)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-(3,6-dihydro-2H-pyran-4-yl)-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene. Tetrahydrofurane is used instead of toluene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH2:11][C:12]#[N:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>O1CCCC1>[CH3:24][C:23]1[C:18]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][C:12]#[N:13])=[N:19][CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CCOC(=O)C(CC#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(C(=O)OCC)c1ncc([N+](=O)[O-])cc1C

Procedure:
2-(Cyanomethyl)malonic acid diethyl ester (G. Casini et al, Ann. Chim. (Rome), 51, 366-74 (1961) (81 g) was reacted with sodium hydride (8.9 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (G.E. Hawkins and A. Roe, J. Org. Chem., 14, 328 (1949)) (58.5 g) was added and the internal temperature was raised to 95°-105° C. (some tetrahydrofuran was distilled off) over 11 hours. The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3), the chloroform extracts were dried and concentrated in vacuo to give an oil (132 g). The oil was distilled under vacuum, the distillate collected at 60°-98° C. (vapour temp.) 0.2 mm Hg was discarded. The residues from the distillation (65 g) were dissolved in chloroform and filtered through a silica column and then concentrated, treated with charcoal and recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (30 g) m.p. 78°-80° C.
Reaction SMILES: C(C1C=CC(N2CC[C@H](N[C@@H](C3C4C(=CC=CC=4)C=CC=3)C)C2)=CC=1)(=O)C.[C:28]1([C@H:38]([NH:40][C@H:41]2[CH2:45][CH2:44][N:43]([C:46]3[CH:58]=[CH:57][C:49]([C:50]([O:52]C(C)(C)C)=[O:51])=[CH:48][CH:47]=3)[CH2:42]2)[CH3:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O.C(Cl)(Cl)[Cl:67]>>[ClH:67].[C:28]1([C@H:38]([NH:40][C@H:41]2[CH2:45][CH2:44][N:43]([C:46]3[CH:47]=[CH:48][C:49]([C:50]([OH:52])=[O:51])=[CH:57][CH:58]=3)[CH2:42]2)[CH3:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)OC(C)(C)C)cc2)C1)c1cccc2ccccc12
Reactant: ClC(Cl)Cl
Agent: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In the same manner as in the above-mentioned Example 1.001, tert-butyl 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoate (the compound of Example 1.020 in the following Table A2) was obtained. (2) To a solution of 103 mg of tert-butyl 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoate in 5 ml of a chloroform was added 20 ml of trifluoroacetic acid, and the mixture was stirred under room temperature for 16 hours. The reaction mixture was concentrated, toluene was added to the residue and the mixture was evaporated again. The residue was dissolved in 10 ml of chloroform, 20 ml of a solution of 4M hydrochloric acid in dioxane was added and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and after collecting the precipitates by filtration, it was washed with diethyl ether and dried to obtain 89.2 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (Example 3.001 in the following Table A3).
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C(Cl)C=1O.C([Zn]CC)C.C(I)I.[CH2:19]=[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[O:30][CH2:31][O:32][CH3:33])[O:23][CH2:22][CH2:21]1>C(Cl)Cl.CCCCCC>[CH3:33][O:32][CH2:31][O:30][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[O:23][CH2:22][CH2:21][C:20]3([CH2:2][CH2:19]3)[C:29]=12
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: C=C1CCOc2cccc(OCOC)c21
Agent: CC[Zn]CC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: ICI
Product: COCOc1cccc2c1C1(CCO2)CC1
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To a solution of 2,4,6-trichlorophenol (307 mg, 1.557 mmol) in 12.0 mL of DCM, at −40° C., 1M solution in hexane of diethylzinc (1.557 mL, 1.557 mmol) was added. After stirring at that temperature for 15 minutes, CH2I2 (0.126 mL, 1.557 mmol) was added. After stirring for additional 15 minutes, 4-methylidene-5-{[(methyloxy)methyl]oxy}-3,4-dihydro-2H-chromene (169 mg, 0.819 mmol) dissolved in 3.0 mL of DCM was added. The cold bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with a 10% aqueous solution of HCl 2 times, then with an aqueous saturated solution of NaHCO3 2 times, an aqueous saturated solution of Na2SO3 2 times and brine (2 times). The organic layer was then dried over Na2OS4, filtered and evaporated and the residue was purified by flash chromatography (Biotage SP1) on silica gel using cyclohexane/ethyl acetate from 100:0 to 95:5. Collected residue was dissolved in DCM and washed (two times) with KOH (30% aq sol). The organic layer was dried over sodium sulphate, filtered and evaporated to afford the title compound (145 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:8]2=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=[C:7]2[NH:6][C:5]=1[C:15]([OH:17])=O.[CH:18]([N:21](C(C)C)CC)(C)C.[C:27]([O:30]C(=O)C)(=O)[CH3:28].[OH-].[Na+].Cl>C(OCC)C.O1CCCC1>[C:27]([NH:1][CH2:2][CH2:3][C:4]1[C:8]2=[N:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=[C:7]2[NH:6][C:5]=1[C:15]([NH:21][CH3:18])=[O:17])(=[O:30])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]c(C(=O)O)c(CCN)c2n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(=O)c1[nH]c2ccc(OC)nc2c1CCNC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-aminoethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (123 mg) and tetrahydrofuran (2.00 mL) were added diisopropylethylamine (0.448 mL) and acetic anhydride (0.074 mL), followed by stirring at room temperature overnight. To the mixture was added a 1 M aqueous sodium hydroxide solution (3.00 mL), followed by stirring for 1 hour, and then 1 M hydrochloric acid (3.00 mL) was added thereto, followed by concentrating under reduced pressure. The residue was suspended in ethanol, the insoluble materials were separated by filtration, and then the filtrate was concentrated under reduced pressure. To a mixture of the obtained residue (144 mg), methylamine hydrochloride (175 mg), diisopropylethylamine (0.622 mL), and N,N-dimethyl formamide (4.65 mL) was added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (592 mg), followed by stirring at room temperature overnight. To the mixture was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 20:1) and the obtained crude product was solidified with diethyl ether and the obtained solid was collected by filtration and dried under reduced pressure to obtain 3-(2-acetamidoethyl)-5-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (81.0 mg) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[C:35]1([NH:41][CH2:42][CH2:43][NH2:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[NH:41]([CH2:42][CH2:43][NH:44][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][CH:21]=1)(=[O:27])=[O:26])=[O:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCCNc1ccccc1
Product: CON=C1C[C@@H](C(=O)NCCNc2ccccc2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]4-sulfonyl chloride, and N1-phenyl-1,2-ethanediamine, the title compound was obtained in 73% purity by HPLC. MS(ESI+): m/z=493.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: Cc1ccccc1B(O)O
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: COCCOC
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 68.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), o-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.047 g (68%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:8]2=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:11](=[O:12])[C:7]2=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:5]1.Cl[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27]>O1CCCC1>[CH2:29]([O:28][C:26]([N:10]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]2[C:7](=[C:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:5]([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[C:4]2=[O:3])[C:11]1=[O:12])=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: O=C1NC(c2ccccc2)=C2C(=O)NC(c3ccccc3)=C12
Reactant: CCCCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1C(=O)C2=C(c3ccccc3)N(C(=O)OCCCC)C(=O)C2=C1c1ccccc1
Reaction time: 24 h

Procedure:
0.28 g (0.007 mol) of solid sodium hydride is added to a suspension of 0.5 g (0.00175 mol) of 1,4-diketo-2,5-dihydro-3,6-diphenyl-pyrrolo[3,4-c]pyrrole in 17 ml of tetrahydrofuran in an argon atmosphere. After the resulting mixture is stirred for 24 hours, 0.67 ml (0.007 mol) of n-butyl chloroformate is added thereto, and the resulting suspension is stirred overnight. The mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is taken into water/diethyl ether, and the organic phase is dried over MgSO4 and then concentrated under reduced pressure. The residue is taken into n-hexane, and the yellow powder precipitated is collected by filtration, washed with a small amount of n-hexane to give 0.62 g (73% of the theoretical value) of N,N'-bis(n-butoxycarbonyl)-1,4-diketo-2,5-dihydro-3,6-diphenyl-pyrrolo[3,4-c]pyrrole as a yellow fluorescent powder.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.ClCCCN1CCC(C2C=CC=CC=2)CC1.C1(C2CCN([CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=4)[NH:47][C:46]3=[O:63])CC2)C=CC=CC=1.C1(C2(C3C=CC=CN=3)NC(=O)NC2=O)C=CC=CC=1>>[C:9]1([CH:6]2[CH2:7][CH2:8][N:3]([CH2:2][CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=4)[NH:47][C:46]3=[O:63])[CH2:4][CH2:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCN1CCC(c2ccccc2)CC1
Reactant: O=C1NC(c2ccccc2)(c2ccccn2)C(=O)N1CCN1CCC(c2ccccc2)CC1
Agent: ClCCCN1CCC(c2ccccc2)CC1
Agent: O=C1NC(=O)C(c2ccccc2)(c2ccccn2)N1
Product: O=C1NC(c2ccccc2)(c2ccccn2)C(=O)N1CCCN1CCC(c2ccccc2)CC1

Procedure:
Analysis -- Calculated for C32H34N4O6 : C, 67.36; H, 6.00; N, 9.82. Found: C, 67.60; H, 6.16; N, 10.01. Substitution of 1-(2-chloroethyl)-4-phenyl-piperidine or 1-(chloromethyl)-4-phenyl-piperidine for 1-(3-chloropropyl)-4-phenyl-piperidine in the above example respectively yields: 3-[2-(4-phenyl-1-piperidyl)ethyl]-5-phenyl-5-(2-pyridyl)-hydantoin and 3-[(4-phenyl)-1-piperidyl)methyl]-5-phenyl-5-(2-pyridyl)-hydantoin.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3]Cl.[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH3:13])[CH:7]=1.[OH-:14].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:10][C:11]([O:14][CH2:9][CH2:8][CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([CH3:13])=[CH:7][CH:6]=2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1ccc(O)cc1
Reactant: ClCCCCl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(OCCCOc2ccc(C)cc2)cc1
Yield: 73.2 %

Procedure:
Operation was carried out in the same manner as in Example 2, using 1,3-propylene dichloride (108 g, 0.96 mol), p-cresol (205 g, 1.90 mol), water (35 ml) and a 49% aqueous solution of NaOH (106 g, 1.30 mol; a first dropwise addition) and further 79 g, 0.97 mol (a second dropwise addition), to obtain 1,3-di(4-methylphenoxy)propane in the form of white plate crystals (178 g). Yield: 73.2% based on p-cresol. M.P.: 93.5° C. Purity: 99.6%.
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][OH:10])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:2].[C:11](Cl)(=[O:15])/[CH:12]=[CH:13]/[CH3:14].[Na+].[Cl-]>C(Cl)(Cl)Cl>[C:11]([O:10][CH2:9][C:3]1([CH2:1][CH3:2])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]
Reactant: C/C=C/C(=O)Cl
Reactant: CCC1(CO)COC(=O)N1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C/C=C/C(=O)OCC1(CC)COC(=O)N1

Procedure:
3.1 grams (0.021 mole) 4-ethyl-4-hydroxymethyl-2-oxazolidinone, prepared identically to that discussed in example 1, 2.3 grams (0.022 mole) trans-crotonyl chloride, and 25 milliliters chloroform were mixed in a one-necked round-bottom flask. The procedure employed was identical to that discussed in example 1. 4.20 grams (98% of the yield theoretically expected) of pure product was obtained as a clear oil The product exhibited the following spectral data: 1H NMR (CDCl3) δ0.90(t, 3H J=1.8 Hz), 1.48-1.67 (m, 2H), 1.83(d, 3H J=3.6 Hz), 3.97-4.19(m, 4H), 5.79(d, 1H J=3.6 Hz), 6.90-6.99(m, 2H); 13C NMR (CDCl3) δ7.3, 18.1, 28.3, 60.2, 66.7, 70.9, 121.7, 146.3, 159.6, 166.0; IR (NaCl) 3229, 3020, 2960, 1780 cm-1 ; MS m/z 213. This monomer can be chlorinated or brominated by the same procedure as in example 1.
Reaction SMILES: [C:1]([NH:20][S:21](=[O:46])(=[O:45])[O:22][CH2:23][C@@H:24]1[C@@H:31]2[C@@H:27]([O:28][C:29]([CH3:33])([CH3:32])[O:30]2)[C@H:26]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[CH2:43][NH2:44])[O:25]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][O:48][C:49]1[CH:57]=[CH:56][CH:55]=[CH:54][C:50]=1[C:51](Cl)=[O:52]>>[C:1]([NH:20][S:21](=[O:45])(=[O:46])[O:22][CH2:23][C@@H:24]1[C@@H:31]2[C@@H:27]([O:28][C:29]([CH3:33])([CH3:32])[O:30]2)[C@H:26]([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[CH2:43][NH:44][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][CH:56]=[CH:57][C:49]=2[O:48][CH3:47])[O:25]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(CN)ncnc21
Product: COc1ccccc1C(=O)NCc1ncnc2c1ncn2[C@@H]1O[C@H](COS(=O)(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@H]21

Procedure:
The title compound was prepared following the procedure described in Example 127, step a using {(3aR,4R,6R,6aR)-6-[6-(aminomethyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}methyl tritylsulfamate and 2-methoxybenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26][CH3:27])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][C:19](=O)[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.[BH4-].[Na+]>ClC(Cl)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:26][CH3:27])[C:10](=[O:25])[N:11]3[CH2:21][CH2:20][CH:19]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:18][N:17]([CH3:23])[C:16](=[O:24])[C:12]3=2)[C:7]1=[O:28]
Reactant: COc1c2c(c3n(c1=O)CCC(=O)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: C1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1c2c(c3n(c1=O)CCC(N1CCCC1)CN(C)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H, 1H)-tetrone (30 mg, 0.06 mmol), molecular sieves (4A), pyrrolidine (23 mg, 0.32 mmol), and acetic acid (4 mg) in dichloroethane (1 mL) was heated at 80° C. for four hrs. The mixture was cooled to room temperature, treated with sodium borohydride (12 mg, 0.19 mmol), and stirred at room temperature for 30 minutes. The product mixture was diluted with dichloromethane, washed successively with aq sodium carbonate and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound. This material was used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:3][C:2]=1[NH:1][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCN(c2ccc(OCc3ccccc3)c(Nc3ccccc3)c2)CC1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a stirred solution of (4-(3-amino-4-(benzyloxy)phenyl)piperazin-1-yl)(phenyl) methanone (1 g, 2.58 mmol) and phenylboronic acid (0.94 g, 7.74 mmol) in DCM (100 mL) was added triethylamine (1.0 mL, 7.74 mmol) and Cu(OAc)2 (0.7 g, 3.87 mmol). The mixture was stirred for 12 h. It was then filtered through celite, evaporated under vacuum. Flash column chromatography gave (4-(4-(benzyloxy)-3-(phenylamino) phenyl) piperazin-1-yl) (phenyl)methanone (0.87 g), 82% yield. 1H NMR (500 MHz, DMSO): δ 3.01 (bs, 2H), 3.16 (bs, 2H), 3.59 (bs, 2H), 3.95 (bs, 2H), 5.10 (s, 2H), 6.20 (s, 1H), 6.42 (dd, J=2.5, 3 Hz 1H), 6.91 (d, J=8.5 Hz, 1H), 7.01 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.32 (m, 2H), 7.37 (m, 10H). HRMS (ESI) calculated for C30H30N3O2: 464.2333, Found: 464.2338.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2CC3[C:13]([C:2]=12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].IC.O>O1CCCC1>[CH3:14][C:15]1([CH3:18])[C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[C:13]2[C:16]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2c(c1)Cc1cccnc1-2
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2ncccc21
Temperature: -10 °C
Reaction time: 6 h

Procedure:
13.5 g (80.7 mmol) of 5H-indeno[1,2-b]pyridine was dissolved in 120 ml dry tetrahydrofuran, and 22.7 g (202 mmol) of potassium tert-butoxide was added to the solution at −10° C. The reaction mixture was maintained at −10° C. for 1 hour. Then the iodomethane 28.7 g (202 mmol) was added dropwise; the solution was then warmed slowly to room temperature and stirred for 6 h. After the reaction completion, water was added to the mixture to terminate the reaction. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the residue was crystallized with toluene to give the 5,5-dimethyl-5H-indeno[1,2-b]pyridine, 13.5 g (86%)