Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][CH2:9]2)=[CH:5][C:4]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([S:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[C:20]#[N:21]>>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([C:19]([S:32][C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:8]2[CH2:7][C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[C:4]([OH:12])[CH:5]=3)[CH2:9]2)[C:20]#[N:21])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1cc2c(cc1O)CNC2
Reactant: COc1ccc(C(C#N)(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1)C2
Yield: 74.2 %

Procedure:
The procedure of Example 49 is used with 0.209 g of 2,3-dihydro-6-methoxy-1H-isoindol-5-ol (Example 105) and 0.57 g of α-(5-bromopentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile. This affords 0.5 g of the desired product as a gray foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:31])[C:28]([NH2:30])=[O:29]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([CH:27]([CH3:31])[C:28]([NH2:30])=[O:29])[CH2:11][CH2:10]2
Reactant: CC(Br)C(N)=O
Reactant: Fc1cccc(COc2ccc3c(c2)CCNC3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C(N)=O)N1CCc2cc(OCc3cccc(F)c3)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a mixture of 6-(3-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline (0.200 g, 0.78 mmol) and potassium carbonate (0.215 mg, 1.56 mmol) in acetone, 2-bromo-propionamide (0.142 mg, 0.936 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture, after filtration and evaporation, was purified by chromatography (SiO2, hexane/Et2O 3:2 v:v) to give the title compound as a white solid (0.189 g, 74%). MS: m/e=329.3 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C@H:23]([CH2:35][OH:36])[CH2:24][CH2:25][N:26]3[CH2:33][CH2:32][C:29]4([CH2:31][CH2:30]4)[C@H:28]([OH:34])[CH2:27]3)[C:19](=[O:37])[C@@H:18]2[CH3:38])=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(NCC)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[O:36][CH2:35][C@@H:23]([N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[NH:14][C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[C@@H:18]([CH3:38])[C:19]1=[O:37])[CH2:24][CH2:25][N:26]1[CH2:33][CH2:32][C:29]2([CH2:31][CH2:30]2)[C@H:28]([OH:34])[CH2:27]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1C(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: CCNCC
Solvent: ClCCl
Product: COC(=O)OC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)Nc2ccc(Cl)c(Cl)c2)[C@@H](C)C1=O
Temperature: 0 °C
Yield: 93.3 %

Procedure:
Methyl chloroformate (9 mg, 0.1 mmol) was added at 0° C. to a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (example 106; 50 mg, 0.10 mmol) in dichloromethane (1 mL). The ice bath was removed, then after 30 min the reaction mixture was cooled to 0° C., treated with diethylamine (4 mg, 50 μmol), and evaporated. Chromatography (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) provided the title compound (52 mg, 93%). White solid, MS (ISP)=557.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][CH:6]1[C:11]([CH3:13])([CH3:12])[CH:10](O)[CH2:9][CH2:8][NH:7]1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH:6]3[C:11]([CH3:13])([CH3:12])[CH:10]([C:15]=2[CH:16]=[CH:17][CH:18]=1)[CH2:9][CH2:8][NH:7]3
Reactant: COc1ccccc1CC1NCCC(O)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1CC1NCCC2C1(C)C
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(2-methoxy-benzyl)-3,3-dimethyl-piperidin-4-ol (0.80 g) in polyphosphoric acid (10 mL) is stirred at 120° C. overnight. After cooling the solution to ca. 80° C., water (300 mL) is added and the mixture is stirred vigorously for another 10 min. Then, the mixture is cooled in an ice bath, more water is added, and the mixture is basified using 10 M aqueous NaOH solution. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are washed with brine and dried (MgSO4). The solvent is removed under reduced pressure to yield the title product that is used without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:46])[NH:6][C:7]2[CH:44]=[CH:43][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:45])[CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:44]=[CH:43][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:45])[CH:8]=2)=[O:46])[CH2:2][CH2:3]1
Reactant: COCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Yield: 86.7 %

Procedure:
Compound 330 (0.15 g, 0.23 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (0.9 mL) and the reaction mixture was stirred for 12 h at r.t. The mixture was concentrated and the residue was purified by Gilson reverse phase HPLC (40-80% MeOH/H2O, Aquasil C18, 30 min) and lyophilized. The purified product (containing some formic acid from the HPLC) was partitioned between warm dichloromethane and 1M NaOH. The organic phase was dried (MgSO4), filtered and concentrated to give title compound 331 (0.110 g, 72% yield) (a mono-TFA salt despite the treatment with NaOH). 1H NMR (DMSO-d6) δ (ppm) 1H: 8.84 (s, 1H); 8.65 (d, J=1.3, 1H); 8.53 (d, J=5.5, 1H); 8.37 (s, 1H); 8.30 (d, J=8.2, 1H); 7.99 (dd, J=8.2, 2.0, 1H); 7.73 (dd, J=13.7, 2.5, 1H); 7.38 (t, 1H); 7.22-7.18 (m, 1H); 6.68-6.64 (m, 2H); 4.03 (s, 2H); 3.60-3.52 (m, 4H); 3.48-3.44 (m, 2H); 3.25 (s, 3H); 2.92-2.88 (m, 2H); 2.55 (septet, J=3.1, 1H); 0.69-0.62 (m, 2H); 0.44-0.40 (m, 2H). LRMS: (M+H): 552.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[O:10])[CH:3]=1.CO[CH:13](OC)[CH2:14][NH2:15]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:14][NH:15][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: COC(CN)OC
Solvent: ClCCl
Product: O=c1[nH]ccn1-c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-bromo-3-isocyanatobenzene (1.0 mL, 8.01 mmol) and [2,2-bis(methyloxy)ethyl]amine (0.86 mL, 8.01 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 16 hr. The solution was concentrated in vacuo and the residue taken up in a mixture of CH3CN (10 mL) and H2O (3 mL). TFA (3 mL) was added and the solution stirred at room temperature for 4 hr. The solution was concentrated in vacuo, the residue taken up in EtOAc then washed with satd NaHCO3, H2O, and brine. The organics were then dried over Na2SO4, concentrated in vacuo and the residue recrystallized from EtOAc to give 1-(3-bromophenyl)-1,3-dihydro-2H-imidazol-2-one as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.60 (d, J=3.0 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 7.34-7.36 (m, 2H); 7.70-7.72 (m, 1H), 8.06 (s, 1H), 10.39 (br s, 1H).
Reaction SMILES: Cl.[OH:2][NH2:3].[OH-].[K+].[Cl:6][C:7]1[C:11]([C:12](Cl)=[O:13])=[C:10]([Cl:15])[N:9]([CH3:16])[N:8]=1.Cl>O.O1CCCC1>[Cl:6][C:7]1[C:11]([C:12]([NH:3][OH:2])=[O:13])=[C:10]([Cl:15])[N:9]([CH3:16])[N:8]=1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Cl)c(C(=O)NO)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
In a solution of hydroxyamine hydrochloride (106.9 g, 1.538 mol) in water (200 ml), a solution of 85% potassium hydroxide (101.5 g, 1.538 mol) in water (200 ml) was added at 5 to 15° C., and stirred at room temperature for 5 minutes. Then, a solution of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride (100.0 g, 0.5128 mol) in tetrahydrofuran (170 ml) was added dropwise at 3 to 8° C. over 2 hours. After stirring at 5° C. for 0.5 hour, the mixture was adjusted to pH 3-4 by adding 35% hydrochloric acid. Precipitated solid was filtered off, washed with water, and dried to obtain the aimed product (94.9 g). Melting point 200-202° C. (decomposition). Proton nuclear magnetic resonance chemical shift values δ (ppm) (in dimethylsulfoxide-d6) 3.79 (s, 3H), 9.24 (brs, 1H), 10.83 (brs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[CH3:44][N:45]1[CH:50]2[CH2:51][CH2:52][CH:46]1[CH2:47][CH:48](O)[CH2:49]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][CH:48]1[CH2:49][CH:50]2[N:45]([CH3:44])[CH:46]([CH2:52][CH2:51]2)[CH2:47]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: CN1C2CCC1CC(O)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1C2CCC1CC(OC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (400 mg, 1.59 mmol) in THF (20 ml), were added N,N′-methanediylidenedicyclohexanamine (394 mg, 1.91 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (258 mg, 1.91 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-ol (270 mg, 1.91 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The residue was taken up with DCM, the insoluble was filtered off, and the clear solution was washed twice with aq. Na2CO3 and brine, dried over Na2SO4 and evaporated to give 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (460 mg; 77% yield). The product was used in the next step without any further purification.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH3:18].C1(C)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:7][S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2)[CH3:18]
Reactant: O=C1c2ccccc2CSc2ccccc21
Reactant: CCNCCCN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCNCCCN=C1c2ccccc2CSc2ccccc21

Procedure:
9.1 g. of dibenzo[b,e]thiepin-11(6H)-one are mixed, while stirring, with 40 g. of N-ethyl-1,3-propanediamine and 250 ml. of absolute toluene and treated dropwise at 0° C. with 8.8 ml. of titanium tetrachloride. The reaction mixture is stirred at room temperature for 18 hours, then cooled and hydrolyzed with 250 ml. of water. The resulting suspension is filtered through diatomaceous earth and the aqueous phase is extracted with toluene. The combined toluene extracts are dried over sodium sulfate and evaporated under reduced pressure. Raw N-ethyl-N'-{dibenzo[b,e]thiepin-11(6H)-ylidene}-1,3-propanediamine is obtained which can be used directly in the above reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:14]([C:12]3[S:13][C:9]([S:8][C:7]4[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=4[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=3)=[O:15])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Nc1ccc2c(c1)OCO2
Product: O=C(Nc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and benzo[d][1,3]dioxol-5-ylamine (53 mg, 0.39 mmol). The title compound was obtained as a solid (28 mg, 44% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.43 (1H, m), 9.00 (2H, s), 8.67 (1H, s), 7.29 (1H, m), 7.06 (1H, m), 6.91 (1H, m), 6.04 (2H, s). MS m/z: 468.04, 470.04 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccccn2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccn4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-2-yl-1,3-dihydroindol-2-one (31.5 mg, 0.15 mmol), 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (48.2 mg, 0.15 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 70° C. for 6 hours. The reaction was concentrated and the residue was re-crystallized from ethyl acetate and hexane to give the title compound.
Reaction SMILES: [C:1]1(=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:15]O.Cl>>[CH3:15][O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:14])=[CH:6][CH:7]=1)=[O:13]
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)C(=O)CCC2
Agent: Cl
Product: COC(=O)c1ccc2c(c1)C(=O)CCC2
Temperature: 0 °C
Yield: 48.6 %

Procedure:
Part A--A mixture of 1-tetralon-7-carboxylic acid (7.0 g, 0.037 mol) in methanol (13.6 mL, 10.8 g, 0.30 mol) with a catalytic amount of hydrochloric acid (0.07 mL, 0.12 g, 0.0012 mol) was stirred at reflux over 5 hours. The cooled reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were backwashed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting solid was purified by flash chromatography using hexane:ethyl acetate::75:25. The resulting solid was triturated with hexane to give 1-tetralon-7-carboxylic acid methyl ester (3.61 g, 0.018 mol, 49%) as a yellow solid. mp=170°-172° C.; 1H NMR (CDCl3) d 8.7 (s, 1H), 8.15 (d, 1H, J=8.1 Hz), 7.35 (d, 1H, J=8.1 Hz), 3.95 (s, 3H), 3.05 (d, 2H, J=6.1 Hz), 2.7 (t, 2H, J=6.4 Hz), 2.15 (quintet, 2H, J=6.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC(C)c1ccc(N)cc1
Product: Cc1ccc(CNc2ccc(C(C)C)cc2)c(C)c1
Yield: 97.8 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 2,4-dimethylbenzaldehyde (1.3 g) and 4-isopropylaniline (1.4 g) as starting material, [(2,4-dimethylphenyl)methyl](4-isopropylphenyl)amine (2.4 g) was obtained.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[CH:19][C:20](=[O:21])[CH3:22])=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C=Cc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In a 250 ml single neck flask was charged 12.1 g (100 mmoles,1.0 eq) of p-tolualdehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.5 g of 4-(p-tolyl)-3-buten-2-one as a faintly yellow oil in 84.3% yield.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:21][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(Cc2nc3ccccc3n2C)cc1
Temperature: 0 °C
Yield: 28 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (0.2 g, 0.75 mmol) in acetone was treated with potassium carbonate (0.31 g, 2.2 mmol), cooled to 0° C., treated dropwise with and methyl iodide (0.070 mL, 1.1 mmol), heated at 40° C. for 12 h, cooled to room temperature, and filtered. The filtrate was evaporated under reduced pressure. Purification of the resultant residue by column chromatography (silica, chloroform) afforded the title product (28%). 1H NMR (400 MHz, CDCl3): 7.98 (d, J=8.4 Hz, 2H), 7.7 (m, 1H), 7.37 (m,5H), 4.38 (s, 2H), 3.9 (s, 3H), 3.5 (s, 3H). [M+H] 281.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[NH:16][C:17]([CH2:19]Cl)=[O:18]>[N+](C)([O-])=O>[CH2:1]([C:3]1[N:7]([CH2:19][C:17](=[O:18])[NH:16][C:10]2[C:9]([CH3:8])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:15])[CH2:6][CH2:5][N:4]=1)[CH3:2]
Reactant: CCC1=NCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: C[N+](=O)[O-]
Product: CCC1=NCCN1CC(=O)Nc1c(C)cccc1C

Procedure:
In a manner similar to Ex. IA react 47.7 gm. (0.486 M) of 2-ethyl-2-imidazoline and 19.21 gm. (0.097 M) of 2-chloro-2',6'-acetoxylidide in 200 ml. of nitromethane, to obtain the title compound.
Reaction SMILES: [N:1]1([C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[NH:8][CH:9]=[N:10]3)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O[C@@H:19]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:20]1[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)C.C([O-])(O)=O.[Na+].O>CC#N>[C:22]([O:21][C@@H:20]1[C@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[O:41][C@H:19]1[N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][CH:13]=[N:14][C:6]=2[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: c1cn(-c2ncnc3nc[nH]c23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(-n4ccnc4)ncnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.4 %

Procedure:
6-(Imidazol-1-yl)purine (52 mg, 0.28 mmol) was suspended in a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (160 mg, 0.32 mmol) in dried CH3CN (10 mL). Stannic chloride (0.10 mL, 0.22 g, 0.85 mmol) was added, and the mixture very rapidly became a clear solution. The solution was stirred at ambient temperature for 4 h. NaHCO3 (0.8 g) and H2O (0.1 mL) were added sequentially, and the suspension was stirred for 1 h. The clear solution layer was separated, and the residue was extracted with CH3CN. The extracts and the solution layer were combined, and volatiles were evaporated in vacuo. The residue was chromatographed (CH2Cl2/MeOH, 1:90→1:15) to give 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-6-(imidazol-1-yl)purine (179 mg, quantitative): 1H NMR (500 MHz, CDCl3) δ 4.72 (dd, J=4.3, 12.2 Hz, 1H), 4.88 (br s, 1H), 4.95 (dd, J=3.0, 12.3 Hz, 1H), 6.29 (“t”, J=5.2 Hz, 1H), 6.47-6.50 (m, 2H), 7.24 (s, 1H), 7.35-7.60 (m, 9H), 7.93 (d, J=7.6 Hz, 2H), 8.03 (d, J=7.6 Hz, 2H), 8.07 (d, J=7.6 Hz, 2H), 8.28 (s, 1H), 8.35 (s, 1H), 8.65 (s, 1H), 9.13 (s, 1H); 13C NMR (125 MHz, CDCCl3) δ 165.0, 164.3, 164.1, 152.1, 151.5, 144.9, 142.2, 136.6, 132.9, 132.8, 132.4, 129.7, 128.8, 128.7, 128.2, 127.5, 127.2, 122.0, 116.3, 86.4, 79.9, 72.9, 70.3, 62.3; HRMS m/z 653.1749 (MNa+[C34H26N6O7Na]=653.1761).
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:43][CH:42]=[C:41](B(O)O)[CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:39]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][CH:42]=[C:41]([N:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[C:20]3[N:19]=[C:18]([CH:36]([CH3:38])[CH3:37])[C:17]([CH:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[C:13]([O:15][CH3:16])=[O:14])=[C:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:25]=3[CH2:24]2)[CH:40]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1cccc(-c3ccccc3)c1)CC2(C)C
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
A mixture of Cu(OAc)2 (16 mg, 0.09 mmol) and pyridine (7 μl, 0.09 mmol) in CH2Cl2 (1 mL) was stirred for 5 min. Added to this were methyl 2-(tert-butoxy)-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol), [1,1′-biphenyl]-3-ylboronic acid (17.9 mg, 0.09 mmol) and 34 mg molecular sieves. The resulting mixture was stirred, uncovered, at room temperature for 21 h. The mixture was adsorbed directly onto silica gel and purified by flash column chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-(6-([1,1′-biphenyl]-3-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (10 mg, 37% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.58-7.52 (m, 2H), 7.41-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.27-7.16 (m, 3H), 7.08-6.99 (m, 2H), 6.79-6.70 (m, 1H), 4.88 (s, 1H), 4.01 (d, J=15.6 Hz, 1H), 3.75 (d, J=15.9 Hz, 1H), 3.73 (s, 3H), 3.56 (dt, J=13.1, 6.6 Hz, 1H), 3.49-3.41 (m, 1H), 3.38-3.30 (m, 1H), 1.59 (s, 1H), 1.51 (d, J=4.0 Hz, 6H), 1.35 (s, 3H), 1.17 (d, J=6.7 Hz, 3H), 1.02 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −113.64. LCMS (M+H) calcd for C38H44FN2O3: 595.33. found: 595.4.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1)=[O:10]
Reactant: N#CC1(c2ccc(N)cc2)CCC1
Reactant: Nc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: N#CC1(c2ccc(NC(=O)c3ccccc3N)cc2)CCC1

Procedure:
A mixture of anthranilic acid (1.4 g) and 1-(4-aminophenyl)cyclobutane-carbonitrile (1 eq) and TEA (1.2 eq) in dichloromethane (80 ml) was stirred with EDCI (1.25 eq) and HOBt (1 eq) at RT overnight. The reaction was washed with sat. NaHCO3, H2O followed by brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give (2-aminophenyl)-N-[4-(cyanocyclobutyl)phenyl]-carboxamide.