Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=O)=[C:11]([NH2:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].O=[C:24]([CH3:35])[CH2:25][CH:26]([CH2:32][CH2:33][CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl[Si](C)(C)C.O>CN(C=O)C>[C:1]([N:4]1[CH2:5][C:6]2[S:12][C:11]3[N:13]=[C:24]([CH3:35])[C:25]([CH:26]([CH2:32][CH2:33][CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:7]=2[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCCC(CC(C)=O)C(=O)OCC
Reactant: CC(=O)N1CCc2c(sc(N)c2C(=O)c2ccc(C)cc2)C1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C(C)=O)C3
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of (6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone (2 g; 6.36 mmol) and ethyl 4-oxo-2-propylpentanoate (1.3 g; 7 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added chlorotrimethylsilane (3.25 mL; 25.45 mmol). The mixture was stirred in a sealed tube and heated at 100° C. for 48 h. After cooling, water (25 mL) was added and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (0-20%) in dichloromethane furnished 2.79 g (94%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40](O)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][O:47][C@@H:48]1[CH2:52][CH2:51][NH:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40]([N:50]4[CH2:51][CH2:52][C@@H:48]([O:47][CH3:46])[CH2:49]4)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@@H]1CCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)N3CC[C@@H](OC)C3)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with (R)-3-methoxy-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3078.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([NH2:14])=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:25][C:26](=O)[CH2:27][CH3:28]>C(OCC)(=O)C>[NH2:13][C:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:25]=[C:26]([CH2:27][CH3:28])[N:14]=1
Reactant: CCC(=O)CBr
Reactant: N=C(N)NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cn(C(=O)OCc2ccccc2)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
A mixture of N-benzyloxycarbonyl guanidine 2.52 g (13.1 mmol), diisopropylethylamine 1.81 ml (8.7 mmol), 1-bromo-2-butanone 0.89 ml (8.7 mmol) and ethyl acetate 50 ml was stirred at room temperature overnight. The reaction solution was washed with water and aqueous sodium chloride solution and dried on magnesium sulfate. After evaporation of the solvent, the residue was purified by a column chromatography on silica gel and further recrystallized from n-hexane to give 0.71 g of the title compound (yield: 33%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[OH:5].[O:17]=[C:18]1[C:23]2[S:24][CH:25]=[C:26]([S:27](Cl)(=[O:29])=[O:28])[C:22]=2[CH2:21][CH2:20][CH2:19]1>>[OH:5][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:3][N:2]([CH3:1])[S:27]([C:26]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18](=[O:17])[C:23]=2[S:24][CH:25]=1)(=[O:28])=[O:29]
Reactant: CNCC(O)c1ccc(N2CCCC2)cc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Product: CN(CC(O)c1ccc(N2CCCC2)cc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From 2-methylamino-1-(4-pyrrolidine-1-yl-phenyl)-ethanol (the compound of Preparation Example 19) (63 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (70 mg), the title compound (35 mg) was obtained as a colorless amorphous substance, in the same way as Preparation Example 41.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[C:4]1=[O:17].[C:18](Cl)([Cl:20])=[O:19].C(N(CC)CC)C>C1(C)C=CC=CC=1.O1CCCC1>[Cl:20][C:18]([NH:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)[C:4]1=[O:17])=[O:19]
Reactant: O=C(Cl)Cl
Reactant: NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Cl)NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: -33 °C
Reaction time: 12 h

Procedure:
After dilution with 200 ml of tetrahydrofurane, 34 g of 3-amino-1-(3,5-dichlorophenyl)pyrrolidine-2,5-dione hydrobromide (obtained in Example 2b) are added at -20° C. to 104 ml of a 20% solution of phosgene in toluene. Then 27.9 g of triethylamine in 100 ml of tetrahydrofurane are added dropwise at -37° to -28° C. and the reaction mixture is thereafter stirred for a further 12 hours at -33° C. to bring the reaction to completion. The precipitate is collected by filtration at -20° C. and the solution is concentrated. The 3-(N-chlorocarbonylamino)-1-(3,5-dichlorophenyl)pyrrolidine-2,5-dione obtained is used direct for the consequent reaction.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[NH2:11][C:12]1[C:13]([Cl:21])=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][NH2:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:11][C:12]1[C:13]([Cl:21])=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][NH:16][C:4](=[O:5])[C:3]([CH3:8])([C:2]([F:10])([F:9])[F:1])[CH3:7]
Reactant: NCc1ccc(Cl)c(N)c1Cl
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C(=O)NCc1ccc(Cl)c(N)c1Cl)C(F)(F)F
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 2-trifluoromethyl-isobutyric acid (2.85 mg, 18 mmol), 3-amino-2,4-dichloro-benzylamine (3.49 g, 18 mmol), TBTU (5.98 g, 19 mmol), TEA (7.7 mL, 55 mmol) and 65 mLTHF is stirred at 45° C. overnight. The mixture is washed with sat aq NaHCO3-solution and water and the organic phase is dried with Na2SO4, filtered, concentrated and purified by chromatography (silicagel, Cyclohexane:EtOAc 11:1→7:3).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:27][CH2:26][CH2:25][N:24]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[O:7])[CH2:23]1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(C)c([N+](=O)[O-])c3)C2)c1

Procedure:
The compound of Example 30 was prepared according to the general preparation protocol A from 4-methyl-3-nitrobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: Cl[B:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]1([Li])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C(OCC)C>[CH:10]1([B:2]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: ClB(Cl)c1ccccc1
Reactant: [Li]C1C=Cc2ccccc21
Solvent: CCOCC
Product: C1=CC(B(c2ccccc2)C2C=Cc3ccccc32)c2ccccc21
Temperature: 25 °C
Yield: 74.3 %

Procedure:
In 50 ml of diethyl ether, 5.01 g (31.5 mmol) of dichloro(phenyl)borane is cooled to -78° C. and a solution of 7.70 g (63.1 mmol) of indenyllithium in 50 ml of diethyl ether is added dropwise within one hour. After warming to room temperature, the mixture is filtered, and the slightly yellow filtrate is highly concentrated in vacuo. Gradual cooling from 0° C. to -20° C. results in the formation of 7.45 g (74%) of bis(indenyl) (phenyl)borane in the form of colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3/[C:7](=[CH:16]\[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])/[C:6]=2[CH:22]=1.O1CCCC1.C([Li])CCC.[C:33](=[O:35])=[O:34]>CCCCCC>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17]/[CH:16]=[C:7]1\[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[O:10][CH2:11][C:5]2[CH:4]=[CH:3][C:2]([C:33]([OH:35])=[O:34])=[CH:22][C:6]\1=2
Reactant: O=C=O
Reactant: CN(C)CC/C=C1/c2cc(Br)ccc2COc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC/C=C1/c2cc(C(=O)O)ccc2COc2ccccc21

Procedure:
Pure (Z)-3-(9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine (0.78 g., 2.2 mmole), in cold (-70° C.) dry tetrahydrofuran (50 mL), was treated with 2.4 mmole n-butyl lithium in hexane followed by gaseous carbon dioxide by the procedure of Example I, Step c. This provided the desired carboxylic acid which was recrystallized from water to yield 0.15 g. pure Z-isomer, m.p. >205° C. (decomp.) with melting at 210° C. pmr (CDCl3 /D2O) δ: 7.84 (d, J=1.8 Hz, 1H, H10), 7.81 (dd, J=6.4, 1.8 Hz, 1H, H8), 6.94-7.35 (m, 5H, aromatic), 5.78 (t, J=6.9 Hz, 1H, CH=), 5.25 (s, 2H, CH2O), 3.20 (m, 2H, NCH2), 2.80 (s, 6H, NMe2), 2.50-2.90 (m, 2H, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[N+:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33])([O-:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH:17][S:32]([C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=1[N+:19]([O-:21])=[O:20])(=[O:33])=[O:34])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-nitro-4-trifluromethylbenzenesulfonylchloride, the title compound was obtained in a similar yield: mp 97°-105° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 8.4-7.7 (m, 4H, arom), 7.6-6.9 (m, 3H, arom.), 6.03 (br, t, J=5 Hz, 1H, NH), 4.98 (AB system, Δv=0.66, J=14.5 Hz, 2H, CH2 -Tr), 3.87 (d, J=6Hz, 2H, CH2NH). Anal calcd. for C18H14Cl2F3N5O5S; C 40.01%; H 2.61%; N 12.96%. Found: C 40.34%; H 2.84%; N 12.57%.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH2:6]2)[CH2:22][CH2:21]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccccc1N1CCN(C2CCC3(CC2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal (4.68 g, 30 mmol), 1-(2-methoxy-phenyl)piperazine (5.8 g, 30 mmol), sodium triacetoxyborohydride (9 g, 42 mmol) and acetic acid (1.8 ml, 30 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 12 hours. The reaction was quenched with 1N sodium hydroxide (pH>9), and extracted with methylene chloride (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 9.0 g (90%) of product as a semi-solid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1>>[N+:1]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[O:6][CH2:7][CH2:8][C:9]2=[O:16])([O-:4])=[O:2]
Reactant: O=C1CCOc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Product: O=C1CCOc2c1cccc2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 9.5 %

Procedure:
A solution of KNO3 (2.25 g, 22.3 mmol) in CH2SO4 (10 mL) was added dropwise to a stirred solution of 4-chromanone (225) (3.0 g, 20.2 mmol) in CH2SO4 (50 mL) at 0° C. and the mixture stirred at 0° C. for 2 h. The mixture was poured into ice/water (500 mL), stirred 30 min and the precipitate filtered. The solid was washed with water (3×10 mL) and dried. The solid was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give (i) 8-nitro-2,3-dihydro-4H-chromen-4-one (226) (369 mg, 9%) as a white solid: mp (EtOAc/pet. ether) 120-121° C.; 1H NMR δ 8.17 (dd, J=7.8, 1.8 Hz, 1H, H-7), 8.10 (dd, J=8.0, 1.8 Hz, 1H, H-5), 7.12 (dd, J=8.0, 7.8 Hz, 1H, H-6), 4.73 (dd, J=6.5, 6.4 Hz, 2H, H-2), 2.95 (br t, J=6.5 Hz, 2H, H-3). Anal. calcd for C9H7NO4: C, 56.0; H, 3.7; N, 7.3. Found: C, 56.1; H, 3.7; N, 7.3%; and (ii) 6-nitro-2,3-dihydro-4H-chromen-4-one (227) (3.17 g, 81%) as a white solid: mp (EtOAc/pet. ether) 169-171° C.; 1H NMR δ 8.78 (d, J=2.8 Hz, 1H, H-5), 8.32 (dd, J=9.1, 2.8 Hz, 1H, H-7), 7.11 (d, J=9.1 Hz, 1H, H-8), 4.67 (dd, J=6.6, 6.4 Hz, 2H, H-2), 2.91 (dd, J=6.6, 6.4 Hz, 2H, H-3); 13C NMR δ 189.4, 165.7, 142.1, 130.3, 123.7, 120.8, 119.3, 67.6, 37.1. Anal. calcd for C9H7NO4: C, 56.0; H, 3.7; N, 7.3. Found: C, 56.1; H, 3.7; N, 7.4%.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:16]1CCOCC1.ClC(OCC(C)C)=O.N.O1CCOCC1>COCCOC>[C:1]1([N:7]2[C:11]([C:12]([NH2:16])=[O:14])=[CH:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cnnn1-c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: COCCOC
Solvent: C1COCCO1
Product: NC(=O)c1cnnn1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid (1.0 g, 5.6 mmol) and 4-methylmorpholine (0.57 g, 5.6 mmol) in 1,2-dimethoxyethane (5 mL), isobutyl chloroformate (0.77, 5.6 mmol) was added to the mixture. After 30 minutes, ammonia in dioxane (16.8 mL, 8.4 mmol) was added to the reaction. Then it was stirred overnight. The solvent was removed and dissolved in 50 mL of ethyl acetate. The organic layer was washed with brine twice. The organic layer was dried with Na2SO4, filtered and concentrated and used without further purification. MS (m/z) 189 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].CS(O[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C.CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CS(=O)(=O)OCc1ccccn1
Reactant: OCc1csc(-c2ccc3c(c2)OCO3)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COCc2csc(-c3ccc4c(c3)OCO4)n2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
2-(Benzo[3,4-d]1,3-dioxolan-5-yl)-4-hydroxymethyl-1,3-thiazole prepared in Example 20(200 mg, 0.85 mmol) was dissolved in N,N-dimethylformamide(5 ml), and sodium hydride(30.7 mg, 1.28 mmol) was added thereto at 0-5° C. To this mixture was added dropwise 2-(methane sulfonyloxymethyl)pyridine(315 mg) dissolved in 1 ml of tetrahydrofuran, and the resulting mixture was stirred for 2 hours at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture, which was then extracted with a solvent mixture of ethyl acetate/n-hexane(1/1, v/v). The extract was washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The concentrate was subjected to silica gel column chromatography(eluent: ethyl acetate/n-hexane=1/2, v/v) to give the title compound(180 mg, Yield 65%) as an ivory solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:17]([CH3:19])[CH3:18])[C:5]2[CH2:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[OH2:20].OO.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:17]([CH3:19])[CH3:18])[C:5]2[CH2:10][C@H:9]([OH:20])[C@@H:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: CN(C)c1nc(Cl)nc2c1CC=C2c1ccccc1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1nc(Cl)nc2c1C[C@H](O)[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-chloro-N,N-dimethyl-7-phenyl-5H-cyclopenta[d]pyrimidin-4-amine (113 mg) in THF (2 mL) at rt was added borane dimethyl sulfide complex in THF (2.0 M solution, 0.41 mL), and the reaction mixture was stirred at rt for 5 h. Water (0.50 mL) was added carefully, followed by 30% H2O2 (0.50 mL) and 1 N NaOH (1 mL). 5 mL EtOAc was added, and the reaction mixture was stirred at rt for 12 h. The crude product was purified by prep. TLC eluting with 50% EtOAc/Hexanes to give the title compound as a yellowish solid (44 mg). LC-MS (M−H2O+H)+=290.05.
Reaction SMILES: [C:1](Cl)([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.[CH2:21]=[C:22]([CH2:25][OH:26])[CH2:23][OH:24].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:2]1([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:24][CH2:23][C:22](=[CH2:21])[CH2:25][OH:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CO)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of trityl chloride (4.05 g; 14.3 mmol) and 2-methylenepropane-1,3-diol (1.20 mL; 14.3 mmol) in dry CH2Cl2 (20 mL) was added triethylamine (4.0 mL; 28.5 mmol) slowly at room temperature. The reaction was stirred at room temperature for 1 h and then ethyl acetate (100 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was separated and washed by saturated aqueous NaHCO3 and NaCl respectively, and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using ethyl acetate-hexane (1:10˜5) as the eluent to afford 10 as white solid (2.89 g; 62% yield): 1H NMR (400 MHz, CDCl3) δ 7.42-7.48 (m, 6H, six of ArH), 7.27-7.33 (m, 6H, six of ArH), 7.20-7.27 (m, 3H, three of ArH), 5.26 (s, 1H, one of C═CH2), 5.17 (s, 1H, one of C═CH2), 4.13 (d, J=6.1 Hz, 2H, CH2OH), 3.70 (s, 2H, Ph3COCH2), 1.72 (t, J=6.1 Hz, 1H, CH2OH); 13C NMR (100 MHz, CDCl3) δ 145.4, 143.6, 128.3, 127.6, 126.8, 111.6, 87.0, 65.3, 64.5, (8).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Cl[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[N:21][CH:22]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: Cc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c3c(c4ccccc42)CN(C)CC3)cn1
Yield: 10.3 %

Procedure:
A solution of 2,3,4,5-Tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (186 mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324 mg, 2.3 mmol) and 60% NaH (120 mg, 3 mmol) in DMF (3 ml) were heated at 120° C. for 16 h to obtain 30 mg of 2,3,4,5-tetrahydro-2-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole after purification by silica gel chromatography (230-400 mesh) using methanol-dichloromethane gradient.
Reaction SMILES: [CH:1]([CH:14]1[CH2:16][O: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.S(O[CH2:22][CH2:23][NH2:24])(O)(=O)=O>C(O)(C)C.[OH-].[Na+]>[CH:1]([CH:14]1[O:15][CH2:22][CH2:23][NH:24][CH2:16]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc(C(c2ccccc2)C2CNCCO2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 13.4 %

Procedure:
A solution of 2-benzhydryloxirane (631 mg) in isopropyl alcohol (4 ml) was added portionwise to a stirred solution of 2-aminoethyl hydrogensulfate (2.12 g) in a mixture of 20% sodium hydroxide solution (3 ml) at 50° C. The whole was stirred at 100° C. for 6 hours and thereto 40% sodium hydroxide solution (6 ml) was added at 100° C. After being stirred for 18 hours at the same temperature, the mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20:1) to give 2-benzhydrylmorpholine (102 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:20])[N:4]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:5]=[C:6]([CH3:11])[C:7]=1[C:8]([OH:10])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52](=[O:59])[NH:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[CH3:57][C:56]1[CH:55]=[C:54]([CH3:58])[NH:53][C:52](=[O:59])[C:51]=1[CH2:50][NH:49][C:8]([C:7]1[C:6]([CH3:11])=[CH:5][N:4]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:3](=[O:20])[C:2]=1[CH3:1])=[O:10]
Reactant: Cc1cn(C(C)c2ccccc2)c(=O)c(C)c1C(=O)O
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2c(C)cn(C(C)c3ccccc3)c(=O)c2C)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution of 3,5-dimethyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid (0.07 g, 0.26 mmol) in dichloromethane (10 mL) was added EDCI (0.06 g, 0.39 mmol), HOBt (0.05 g, 0.38 mmol) and triethylamine (0.078 g, 0.77 mmol). After stirred for 30 min, 3-(aminomethyl)-4,6-dimethyl pyridin-2(1H)-one (0.058 g, 0.39 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The solution was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The extractions were combined, washed with H2O, dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep. HPLC (Condition: Column: YMC C18 150*30 mm*5 um; Mobile phase A: water with 0.05% ammonia solution Mobile phase B: MeCN; column temperature: 30° C.; Gradient: A/B, 35-65%) to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,5-dimethyl-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxamide as yellow solid. (7.5 mg, yield 7.1%)