Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH2:10][OH:11])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Cl:13][C:14]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=1[CH:16]=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:2]1([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[O:1][CH:16]([C:15]2[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:14]=2[Cl:13])[O:11][CH2:10]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCCOC(=O)C(C)(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C1(C)COC(c2cc([N+](=O)[O-])ccc2Cl)O1
Yield: 101.6 %

Procedure:
19.4 g of n-butyl 2,3-dihydroxyisobutyrate is added to 18.6 g of 2-chloro-5-nitrobenzaldehyde and 0.5 g of p-toluenesulfonic acid in 250 ml of toluene, and the mixture is refluxed for 5 hours using a water separator. The mixture is cooled, the solvent is removed and the remainder is dried in a high vacuum. There is obtained 35 g of 3-(5-methyl-5-n-butyloxycarbonyl-1,3-dioxolan-2-yl)-4-chloronitrobenzene (oil).
Reaction SMILES: B.O1CCCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[F:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34][Cl:35])=[CH:31][CH:30]=1.Cl>C1(C)C=CC=CC=1.ClCCl.CO>[Cl:35][CH2:34][C@H:33]([C:32]1[CH:37]=[CH:38][C:29]([F:28])=[CH:30][CH:31]=1)[OH:36]
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O[C@H](CCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, 60 ml, 60 mmol) was added dropwise over 15 min to a (S)—CBS solution ((S)-2-methyl-CBS-oxazaborolidine, 12 ml, 1.0 M solution in toluene) at −30° C., and the mixture was stirred for 15 min. A solution of 4-fluorophenacyl chloride (10.4 g, 60 mmol) in dichloromethane (16 ml) was added dropwise over 60 min keeping the temperature −32° C. to −28° C. After stirring for 1 hr, the solution was allowed to warm to room temperature, and methanol (20 ml) was added slowly and then 1 M hydrochloric acid (120 ml) was added dropwise over 10 min. The reaction mixture was filtered after stirring for 40 min, and the filtrate was extracted with ethyl acetate. The combined organic layer was washed successively with 1 M hydrochloric acid and brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give 2-chloro-(1S)-1-(4-fluorophenyl)ethanol (10.4 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[N:5]1.C(N(CC)C(C)C)(C)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>ClCCl>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:42]([CH:39]3[CH2:41][CH2:40]3)=[O:43])[N:5]=2)[CH:26]=1
Reactant: COc1ccc(Cl)cc1-c1nn(CCN)cc1NC(=O)c1cnn2cccnc12
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1nn(CCNC(=O)C2CC2)cc1NC(=O)c1cnn2cccnc12
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of N-(1-(2-aminoethyl)-3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.030 g, 0.073 mmol, 1 equiv) and N,N-diisopropylethylamine (51 μL, 0.29 mmol, 4.0 equiv) in dichloromethane (1 mL) was added dropwise cyclopropanecarbonyl chloride (0.020 mL, 0.22 mmol, 3.0 equiv) at 24° C. After 1 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC provided product (16.5 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.69 (s, 1H), 9.33 (dd, J=7.0, 1.6 Hz, 1H), 8.78 (dd, J=4.1, 1.5 Hz, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.22 (t, J=5.5 Hz, 1H), 7.50 (dd, J=8.8, 2.8 Hz, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.27-7.31 (m, 2H), 4.22 (t, J=6.1 Hz, 2H), 3.85 (s, 3H), 3.52 (q, J=6.0 Hz, 2H), 1.55 (m, 1H), 0.62-0.71 (m, 4H). LCMS (ESI): M+H=480.2.
Reaction SMILES: [CH2:1]([O:3]C1N=C(C(O)=O)C=C(CC)N=1)C.C([O:17][C:18]([C:20]1[CH:25]=[C:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1)=[O:19])C.CC([O-])(C)C.[K+]>CO>[CH2:26]([C:24]1[N:23]=[C:22]([O:3][CH3:1])[N:21]=[C:20]([C:18]([OH:17])=[O:19])[CH:25]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1cc(CC(C)C)nc(S(C)(=O)=O)n1
Reactant: CCOc1nc(CC)cc(C(=O)O)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: COc1nc(CC(C)C)cc(C(=O)O)n1

Procedure:
The title compound is obtained as a yellow oil (82 mg) in analogy to 2-ethoxy-6-ethyl-pyrimidine-4-carboxylic acid starting from 6-isobutyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid ethyl ester, KOtBu and methanol; LC-MS: tR=0.77 min, [M+H]+=210.96.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13]Br.[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:17].NC1C=CC=CC=1>>[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:13][C:5]3[C:4](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=3)[C:3]2=[O:15])=[CH:27][CH:28]=1)[CH3:17]
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Solvent: Nc1ccccc1
Product: CCOC(=O)CCCc1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-nitrobenzoic acid methyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[CH2:16][C:17]2[CH:33]=[CH:32][C:20]3[N:21]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[O:23][C:19]=3[CH:18]=2)=[CH:10][N:9]=1)[CH3:7])C.[OH-].[Na+]>CO>[C:26]1([CH3:31])[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:22]1[O:23][C:19]2[CH:18]=[C:17]([CH2:16][C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:35])=[O:3])=[N:9][CH:10]=3)=[O:34])[CH:33]=[CH:32][C:20]=2[N:21]=1
Reactant: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C(C)CC(=O)O)nc3)cc2o1
Reaction time: 3 h
Yield: 21.3 %

Procedure:
A solution of (3RS)-3-{5-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-pyrid-2-yl}-butyric acid ethyl ester (0.3 g, Reference Example 1) in methanol (4 mL) was treated with aqueous sodium hydroxide solution (1.5 mL, 1M) and left to stand in a water bath at 40° C. for three hours. The mixture was partially evaporated, diluted with more water and partially evaporated again. The residue was diluted with water (10 mL) and washed with diethyl ether (10 mL). The pH of the aqueous phase was adjusted to 7 by addition of dilute hydrochloric acid. The resulting white solid was filtered then dried and then triturated with boiling acetonitrile to give the title compound (0.06 g) as a white powder, m.p. 195-196° C. (with decomposition). MS: 445 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:11](I)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:11]2[C:3]([CH2:1][CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCc1nn2ccccc2c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCc1nn2ccccc2c1-c1cc(F)cc(F)c1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
2-Ethyl-3-iodopyrazolo[1,5-a]pyridine (0.5 g, 2.0 mmol) and (3,5-difluorophenyl)boronic acid (0.35 g, 2.2 mmol) [Aldrich 471925] were stirred in dioxane (12 mL). A solution of potassium carbonate (0.29 g, 2.1 mmol) in water (2.8 mL) was added. Tetrakis-(triphenylphosphine)palladium(0) (0.13 g, 0.1 mmol) was added and the mixture was heated at 100° C. for 16 h. After cooling, the mixture was diluted with ethyl acetate and washed with water and brine. The extracts were dried over magnesium sulfate, filtered, concentrated and purified on silica gel with ethyl acetate in hexanes (0-10%) to give the desired compound (0.41 g, 80%). LCMS for C15H13F2N2 (M+H)+: m/z=259.2. 1H NMR (300 MHz, DMSO-d6): δ 8.67 (m, 1 H), 7.64 (m, 1 H), 7.25 (m, 1 H), 7.18 (m, 3 H), 6.90 (m, 1 H), 2.89 (m, 2 H), 1.22 (m, 3 H).
Reaction SMILES: C([N:8]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([C:35](=[O:37])[NH2:36])[CH:29]=1)[CH2:9][CH:10]([OH:24])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C.FC(F)(F)C(O)=O>[C:35]([C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[OH:34])[O:27][CH2:26][CH2:25][NH:8][CH2:9][CH:10]([OH:24])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:17][CH:18]=1)(=[O:37])[NH2:36]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nccs3)cc2)ccc1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(OCCNCC(O)COc2ccc(-c3nccs3)cc2)ccc1O

Procedure:
After the addition of 0.69 g of palladium-on-carbon catalyst (10%), a solution of 3.0 g of crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(thiazol-2-yl)-phenoxy]-2-propanol in a mixture of 30 ml of glacial acetic acid and 3 ml of trifluoroacetic acid is hydrogenated at 45° and normal pressure until the absorption of hydrogen has ceased. The suspension is filtered through a filter aid and the filtrate is freed of solvent; ice water is added to the residue, the pH is adjusted to approximately 9 with ammonia and extraction is carried out several times with ethyl acetate. The combined organic phases are dried over sodium sulphate, concentrated by evaporation and the residue is recrystallised from isopropanol, yielding 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(thiazol-2-yl)-phenoxy]-2-propanol having a melting point of 136°-138°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:23]([CH3:25])[CH3:24])[CH2:13][CH2:12][C:11](CCC3C=CC=CC=3)([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OCC)C.Cl.[OH-].[Na+]>C(OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:23]([CH3:25])[CH3:24])[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN(C)C1(c2ccc(Br)cc2)CCC(O)(CCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Product: CN(C)C1(c2ccc(Br)cc2)CCC(=O)CC1
Yield: 91.2 %

Procedure:
7.48 g 4-(4-bromophenyl)-4-dimethylamino-1-phenethylcyclohexanol were dissolved in 30 ml diisopropylether and 10 ml diethylether and were stirred for 4 days with 13 ml 4-molar hydrochloric acid. To work up the reaction mixture, it was alkalized by addition of sodium hydroxide solution (32% by weight), extracted three times with 30 ml dichloromethane in each case, the combined extracts were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. The 5.02 g 4-(4-bromophenyl)-4-dimethylaminocyclohexanone obtained, dissolved in 22 ml tetrahydrofuran, were added dropwise to 18 ml 1.0 molar phenethyl magnesium chloride solution in THF in a nitrogen atmosphere at ambient temperature and were stirred overnight. To work up the mixture with ice cooling, 28 ml ammonium chloride solution (20% by weight) were added, the phases were separated, the mixture was extracted three times with 25 ml diethylether in each case, the combined organic phases were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. The crude product obtained (5.83 g) was taken up in 50 ml diethylether, extracted three times with 40 ml hydrochloric acid (5% by weight) in each case and the combined extracts were washed twice with 40 ml dichloromethane in each case. The dichloromethane extracts were dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. 3.66 g of a light brown resin were obtained and were chromatographed with diethylether/hexane (V:V=2:1) over silica gel. The 1.38 g 4-(4-bromophenyl)-4-dimethylaminocyclohexanone obtained were dissolved in 20 ml 2-butanone and converted by reaction with 474 μl chlorotrimethylsilane and 34 μl water, stirring overnight with subsequent filtration, diethylether washing and vacuum drying, into 1.47 mg of the corresponding hydrochloride.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Yield: 93.4 %

Procedure:
Following General Procedure D and using 3-bromo-benzoic acid isopropyl ester (Intermediate 135, 1.25 g, 5.14 mmol), triethyl amine (12 mL), copper(I)iodide (0.078 g, 0.41 mmol), trimethylsilyl acetylene (4 mL, 28.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.288 g, 0.41 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 3% ethyl acetate in hexane as the eluent, the title compound (1.25 g, 94%) was obtained as an orange oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18].[CH2:20](C1C2C(=CC=C(OC)C=2)CCC1=O)C>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:19][CH3:20])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:18]
Reactant: CCC1C(=O)CCc2ccc(OC)cc21
Reactant: COc1ccc2c(c1)C(C)(CCCCCl)C(=O)CC2
Product: CCC1(CCCCCl)C(=O)CCc2ccc(OC)cc21

Procedure:
Using a procedure analogous to that described in Example I for the preparation of 1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone there is obtained from 35 g. of 1-ethyl-7-methoxy-2-tetralone; 37.4 g. of the title product b.p. 160°-173° C. (0.4 mm.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:24][CH:25]([Si:27](Cl)([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH3:26].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[N:8]([Si:27]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:26])[CH3:24])[C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 60.7 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (300 mg, 0.85 mmol) was dissolved in DMF (3 mL), and NaH (60% weight dispersion in mineral oil, 40 mg, 1.02 mmol) and TIPSCl (164 mg, 1.02 mmol) were added. After stirring for 1 h, the mixture was poured into water and extracted with EtOAc. Concentration of the organic extracts and purification of the residue by flash column chromatography (silica gel, EtOAc/hexanes) provided the title compound (262 mg, 61%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 1.4 Hz, 1H), 4.59 (s, 2H), 3.76-3.71 (br m, 2H), 2.96-2.90 (br m, 2H), 1.81-1.71 (m, 3H), 1.51 (s, 9H), 1.15 (d, J=7.5 Hz, 18H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C@@H:5]([NH2:35])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:8][CH:7]=1.O1CCCC1.[S:42](Cl)([C:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:50]([N:51]([CH3:53])[CH3:52])[C:49]=2[CH:48]=[CH:47][CH:46]=1)(=[O:44])=[O:43]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C@@H:5]([NH:35][S:42]([C:45]1[C:57]2[C:49](=[C:50]([N:51]([CH3:53])[CH3:52])[CH:54]=[CH:55][CH:56]=2)[CH:48]=[CH:47][CH:46]=1)(=[O:44])=[O:43])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:10][CH:11]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H](NS(=O)(=O)c1cccc2c(N(C)C)cccc12)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A mixture of (R)-3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid methyl ester (0.75 g, Reference Example 30), anhydrous tetrahydrofuran (25 ml), dansyl chloride (0.62 g) and triethylamine (1.0 ml) was placed under an atmosphere of argon and stirred at ambient temperature for 4 hours then heated to reflux for 2 hours. The reaction mixture was cooled then filtered. The filtrate was evaporated and the residue was subjected to flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (49: 1, v/v to give the title compound (0.89 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: COCC(C)Nc1nccc(-c2ccnc(Cl)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COCC(C)Nc1nccc(-c2ccnc(Nc3c(C)cccc3Cl)c2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-chloro-4-pyridinyl)-N-(2-methoxy-1-methylethyl)-2-pyrimidinamine (i.e., the product of Step B) (100 mg, 0.35 mmol) in toluene (10 mL) was added 2-chloro-6-methylaniline (102 mg, 0.72 mmol), cesium carbonate (350 mg, 1.07 mmol), palladium(II) acetate (4 mg, 0.017 mmol) and ((±)-BINAP) (22 mg, 0.035 mmol), and the resulting mixture was stirred at reflux for 30 h. After cooling to room temperature, the mixture was concentrated, and purified using column chromatography on silica gel eluted with 40% ethyl acetate in hexanes to give 30 mg of the title compound as a solid.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].S(Cl)([Cl:17])=O>>[N:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([Cl:17])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=Nc1ccc(C=CC(=O)O)cc1
Product: [N-]=[N+]=Nc1ccc(C=CC(=O)Cl)cc1
Yield: 79.2 %

Procedure:
To 17 g (90 millimoles) of p-azidocinnamic acid was added 53 g (450 millimoles) of thionyl chloride, and the resulting solution was refluxed with heating. When the generation of SO2 gas terminated, the reflux was stopped, after which the excess thionyl chloride was distilled off under reduced pressure to obtain 14.8 g of p-azidocinnamic acid chloride as the distillation residue.
Reaction SMILES: [N:1]1([C:8]2[C:9]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.N1(C2C=CN=CC=2)CCCC1.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C(Cl)Cl>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[N:16]1[CH2:15][CH:14]([C:9]2[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([C:45]([O:46][CH3:47])=[O:48])[CH2:3][CH2:2]3)=[N:13][CH:12]=[CH:11][N:10]=2)[CH2:17]1
Reactant: c1ccc2nc(N3CC(c4nccnc4N4CCCNCC4)C3)ccc2c1
Reactant: COC(=O)Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CCCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a round bottomed flask was added 2-(3-(3-(1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline (0.0772 g, 0.214 mmol), pyridine (commercially available through Aldrich, 0.035 ml, 0.428 mmol), and 4-(pyrrolidin-1-yl)pyridine (commercially available through Alfa Aesar, 0.032 g, 0.214 mmol) and the reaction was allowed to stir at RT in DCM (0.714 ml). Methyl carbonochloridate (commercially available through Aldrich, 0.021 ml, 0.321 mmol) was added and allowed to stir overnight. Upon completion, the solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage 50 g SNAP HP-silica column, eluting with a gradient of 0.5% to 5% MeOH in CH2CL2, to provide methyl 4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate (0.0632 g, 0.151 mmol, 70.5% yield). ESI-MS (M+1): 419.0. PDE10 IC50 (μM): 0.0046.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1(C2C=CC(C(=O)C)=CC=2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:4][CH:5]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(N5CCOCC5)cc4)ccc3c1)n2C1CCCCC1
Yield: 30 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-morpholin-4-yl-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (37 mg, 30% yield). MS: 533.28 (M+H+); HPLC Procedure A, retention time=10.39 min.