Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[Br:47][C:48]1[CH:56]=[CH:55][C:51]([CH2:52][NH:53][NH2:54])=[CH:50][CH:49]=1>CCOC(C)=O>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:16]([NH:54][NH:53][CH2:52][C:51]1[CH:55]=[CH:56][C:48]([Br:47])=[CH:49][CH:50]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NNCc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Cbz-(L)-Valine (1.04 g, 4.14 mmol) was dissolved in EtOAc (50 mL) and EDAC (0.870 g, 4.54 mmol), HOBT (0.610 g, 4.51 mmol), and NMM (0.500 mL, 4.55 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and then 4-bromo-benzylhydrazine (1.00 g, 4.97 mmol) in EtOAc (5 mL) was added and the stirring was continued for 2 h. After evaporation of the solvent, CHCl3 was added and the solution was washed with saturated NaHCO3 (aq.) and brine followed by drying (Na2SO4), filtration and evaporation of the organic solvent. The crude product was purified by column chromatography (silica, CHCl3/MeOH, 100:0-95:5) yielding the title compound (1.42 g, 79%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([OH:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]1([C:24](Cl)=[O:25])[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH3:1][CH:2]([CH:8]([O:10][C:24]([C:11]1[C:23]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:25])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Reactant: CCOC(=O)C(C)C(C)O
Product: CCOC(=O)C(C)C(C)OC(=O)c1cccc2c1Cc1ccccc1-2
Yield: 25 %

Procedure:
0.01 Mole of ethyl 2-methyl-3-fluorenoyloxybutyrate was prepared from 0.04 mol of ethyl 2-methyl-3-hydroxybutyrate and 0.05 mol of fluorenoyl chloride (9-fluorenyl carbonyl chloride) following the procedure as described in step 3) of the Preparation Example 3. Yield 25%.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:22][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[N+:19]([O-])=O)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[H][H]>CO.C1COCC1.[Pd]>[OH:1][CH2:2][C@H:3]1[CH2:22][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[NH2:19])[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)ccc1N1CCN2C[C@H](CO)CC[C@H]2C1
Yield: 97.8 %

Procedure:
A solution of 3.0 g (9.7 mmol) of (7R,9aS)-7-hydroxymethyl-2-(4-fluoro-2-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1 H-pyrido[1,2-a]pyrazine in 50 mL of methanol and 50 mL of THF was treated with 0.30 g of 10% Pd/C and treated with 30 psi of hydrogen in a Parr apparatus for 1.5 h. The catalyst was removed by filtration and the red solution concentrated to give 2.65 g (98%) of (7R,9aS)-7-hydroxymethyl-2-(2-amino-4-fluorophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [H-].[Na+].[CH2:3](I)[CH3:4].[N+:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[NH:12][C:13](=[O:15])[CH3:14])([O-:8])=[O:7].O>CN(C)C=O>[N+:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[N:12]([CH2:3][CH3:4])[C:13](=[O:15])[CH3:14])([O-:8])=[O:7]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
Sodium hydride (50% in mineral oil; 1.44 g.), followed by ethyl iodide (3.6 ml.), were added, in small portions during 2 minutes, to a warm stirred solution of 3',5'-dinitroacetanilide (6.75 g.) in dimethylformamide (20 ml.). The mixture was heated on the steam bath for 150 minutes, then cooled, poured into water (400 ml.) and extracted with ethyl acetate (3 × 100 ml.). The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was purified by chromatography on alumina (150 g.) using benzene as the eluant. The fractions containing the required product were combined, evaporated to dryness and the residue crystallised from ethanol, to give 3',5'-dinitro-N-ethylacetanilide (4.2 g.), m.p. 126°-127°C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.CCCCCCC>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][S:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: OCCOC1c2ccccc2CSc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CSc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
Under a nitrogen atmosphere, 2-(6,11-dihydrodibenzo[b,e]thiepin-11-yloxy)-ethanol (340 mg, 1.25 mmol), tributylphosphine (280 mg, 1.37 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (330 mg, 1.37 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (350 mg, 1.37 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified chromatography eluting with ethyl acetate/heptane (1:4) to give 460 mg (75%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 1.25 (t, 3H), 2.95 (d, 2H), 3.30-3.40 (m, 1H), 3.55-3.65 (m, 1H), 2.85 (t, 2H), 3.95 (t, 1H), 4.10-4.22 (m, 4H), 4.5-5.1 (bs, 1H), 5.60-5.75 (bs, 1H), 6.82 (d, 2H), 7.05-7.50 (m, 10H).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([C:23]([NH2:25])=[O:24])=[CH:20][C:19]=2[CH:26]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>C1(C)C(C)=CC=CC=1>[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21]([C:23]([NH2:25])=[O:24])=[CH:20][C:19]=3[CH:26]=2)[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: NC(=O)c1cc2cc(Br)ccc2o1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1C
Product: NC(=O)c1cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2o1
Temperature: 125 °C
Reaction time: 0.25 h

Procedure:
0.30 g of P(t-Bu)3, 4.5 g of 5-bromobenzofuran-2-carboxamide, 4.9 g of benzylpiperazine and 5.0 g of Na t-OBu are added to a suspension of 0.085 g of Pd(II) acetate in 150 ml of xylene after the latter has been stirred for 15 minutes, and the mixture is warmed at 125° C. for 12-18 hours under the protective gas nitrogen. After cooling, the mixture is added to 500 ml of 2N hydrochloric acid, and the aqueous phase is extracted 3 times with 200 ml of ethyl acetate. The aqueous phase is adjusted to pH 10 using aqueous NaOH (20%) with pH and temperature monitoring (20-25° C.), and the 5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxamide produced as a solid is filtered off and crystallized, for example, from ethanol/water (product weight: 4.0 g/64%/m.p. 277-279°).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]12[CH2:26][CH2:25][CH2:24][C:22]3[C:23]1=[C:18]([CH:19]=[CH:20][CH:21]=3)[NH:17][C:16]2=[O:27]>>[S:1]1[C:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]34[CH2:26][CH2:25][CH2:24][C:22]5[C:23]3=[C:18]([CH:19]=[CH:20][CH:21]=5)[NH:17][C:16]4=[O:27])[CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: c1cc2c(s1)CCNC2
Product: O=C1Nc2cccc3c2C1(CCCCN1CCc2sccc2C1)CCC3

Procedure:
This was synthesized by the same method of Synthesis Example 14c, except that 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine was used instead of 1,2,3,4-tetrahydroisoquinoline and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one was used instead of 2a-(4-bromobutyl)-1-methyl-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (yield, 84%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8](=[O:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H][H]>[Pd].C(#N)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8](=[O:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)CCC(=O)/C=C/c1ccco1
Agent: [Pd]
Solvent: CC#N
Product: CCOC(=O)CCC(=O)CCc1ccco1

Procedure:
In a round bottom flask was placed 1.334 g (6.000 mmol) of (E)-ethyl 6-(furan-2-yl)-4-oxohex-5-enoate. 6 mL of acetonitrile was added and stirring was begun. To this was added 0.064 g Pd/C (en) and hydrogen was added using a balloon (˜1 atm). The reaction mixture was stirred for 48 h and the mixture was then purified by flash column chromatography using 15% ether/hexane, v/v. Purification gave rise to 0.4817 g (73%) of the saturated system 1H (CDCl3) δ 1.25 (t, J=7 Hz, 3H), 2.6 (m, 2H), 2.8 (m, 2H), 2.9 (m, 2H), 3.0 (m, 2H), 4.16 (q, J=7 Hz), 6.0 (1H), 6.3 (1H), 7.3 (1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8][O:7][N:6]=1)[NH2:4].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: CS(=O)(=O)NCCCNc1nonc1C(N)=NO
Reactant: Nc1ccc(F)c(Cl)c1
Product: CS(=O)(=O)NCCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Yield: 10 %

Procedure:
The title compound was prepared according to the procedure of Example 4, step E, using N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide [made according to Example 4, steps A through D] and 3-chloro-4-fluoroaniline [Aldrich, product #228583] as the starting materials in 10% yield. LCMS for C13H17ClFN6O4S (M+H)+: m/z=407.1. 1H NMR (400 MHz, CD3OD): δ 7.06 (t, J=8.9 Hz, 1H), 6.98 (m, 1H), 6.80 (m, 1H), 3.73 (m, 2H), 3.28 (m, 2H), 2.94 (s, 3H), 1.28 (m, 2H).
Reaction SMILES: C(=S)([S-])[S-:2].[Na+].[Na+].[C:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])[CH:8]=[CH2:9]>Cl>[CH2:12]([O:11][C:7](=[O:10])[CH:8]([SH:2])[CH3:9])[CH:13]([CH3:15])[CH3:14]
Reactant: C=CC(=O)OCC(C)C
Reactant: S=C([S-])[S-]
Agent: Cl
Agent: [Na+]
Product: CC(C)COC(=O)C(C)S
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
There were present in a stirring apparatus 577.5 grams of a 40% sodium trithiocarbonate solution (corresponding to 1.5 moles). Under stirring at -10° C. there were dropped in 128 grams of isobutyl acrylate (1.0 mole). Post stirring was continued for a further 10 minutes and then the mixture was acidified with 350 ml of 32% hydrochloric acid. After the phase separation the organic phase was fractionally distilled. There were obtained 128 grams of mercaptopropionic acid isobutyl ester (corresponding to a yield of 79%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[C:24]1([N:30]2[CH:34]=[C:33]([CH2:35][CH2:36][C:37]3[N:38]=[CH:39][S:40][CH:41]=3)[C:32]([OH:42])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:42][C:32]3[C:33]([CH2:35][CH2:36][C:37]4[N:38]=[CH:39][S:40][CH:41]=4)=[CH:34][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: Oc1nn(-c2ccccc2)cc1CCc1cscn1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CCc2cscn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.57 g), 1-phenyl-4-[2-(1,3-thiazol-4-yl)ethyl]-1H-pyrazol-3-ol (0.38 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at room temperature for 4 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-({2-methoxy-4-[({1-phenyl-4-[2-(1,3-thiazol-4-yl)ethyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.53 g, yield 66%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [CH:1](=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5])[CH3:2].C(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])(C)(C)C>O1CCCC1>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:2][CH:1]=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5]
Reactant: CC=C(C#N)c1cccnc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=CC=C(C#N)c1cccnc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A 0.2 g portion of α-ethylidene 3-pyridine acetonitrile and 0.315 ml of t-butoxy-bis-dimethylaminomethane were dissolved in tetrahydrofuran and stirred at 20° C. for 20 hours. The solvent was removed at reduced pressure and the orange oil was purified by chromatography, eluting with ethyl acetate:hexane (10:3). The eluate was concentrated to a solid which was recrystallized from methylene chloride-hexane, giving α-[3-(dimethylamino)-2-propenylidene]-3-pyridineacetonitrile as yellow crystals, mp 117°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:29][C@@H:28]([OH:30])[CH2:27][CH2:26][NH:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31](O)=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>>[CH:31]([N:25]1[CH2:26][CH2:27][C@H:28]([OH:30])[CH2:29][C@@H:24]1[C:10]1[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: O=CO
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2)c(OCc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C=O)c(OCc2ccccc2)c1
Yield: 68.2 %

Procedure:
Using the procedure of Example 14, Part A, 1.81 g (4.42 mmole) of cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol, 206 mg (4.48 mmole) of formic acid and 1.04 g (5.04 mmole) of dicyclohexylcarbodiimide gives 1.32 g (70%) of the corresponding formamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH3:19])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCI
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N,N-dimethylformamide (1.3 mL) was added potassium carbonate (269 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodoethane (305 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (187 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.[S:31](N)([NH2:34])(=[O:33])=[O:32]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][NH:34][SH:31](=[O:33])=[O:32])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: NC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: O=[SH](=O)NNC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-amine (36.6 mg, 0.083 mmol, 1 eq.) in 2 mL of dioxane was added sulfamide (40 mg, 0.42 mmol, 5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield 34 mg (79%) of desired compound. 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.51-1.72 (m, 2 H) 2.15 (br. s., 2 H) 3.38-3.52 (m, 2 H) 3.54-3.65 (m, 1 H) 5.18-5.41 (m, 2 H) 7.24-7.50 (m, 7 H) 7.54-7.67 (m, 1 H) 8.23 (s, 1 H), [M+h]+ 518.5.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24]>C1COCC1.CN(C=O)C>[CH2:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CC(C)CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CNC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Isobutylamine (247 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (102 mg, 71%). NMR 1H (ppm, CDCl3): 7.97 (t, J4=1.71 Hz, 1H), 7.70 (dd, J3=7.65 Hz, J4=1.77 Hz, 2H), 7.62-7.58 (m, 2H), 7.51-7.34 (m, 4H), 6.18 (br. s., 1H), 3.33-3.29 (m, 2H), 1.91 (n, J3=6.71 Hz, 1H), 0.98 (d, J3=6.68 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[N:9]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:34]1([CH:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:31][CH2:32][NH:33][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)N1C(=O)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)NC(C)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
117 mg (0.346 mmol) of 4-(3-chlorophenyl)-3-ethoxycarbonyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 110 mg (0.519 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of dichloromethane. 99.5 mg (0.519 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (1/1) and then dried under reduced pressure to obtain the title compound.
Reaction SMILES: Cl.[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][C:11](=[O:18])[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41]>CN(C=O)C.O>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[CH2:10][C:11](=[O:18])[N:12]2[CH2:13][CH2:14][N:15]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:41])([F:42])[F:43])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(Cc2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
A solution of N-Biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) and K2CO3 (58 mg, 0.42 mmol) in DMF (2 mL) was stirred for 15 minutes at room temperature, then cooled to 0° C. and 1-bromomethyl-2-trifluoromethyl-benzene (50 mg, 0.21 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours then diluted with water. The resulting precipitate was filtered to afford 85 mg (85%) of N-biphenyl-4-yl-3-oxo-3-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-propionamide. LCMS: 482.2 (M+1)+, 98.8%, 1H NMR: (CDCl3): δ 10.0 (s, 1H), 7.76 (d, 1H), 7.66 (d, 3H), 7.58 (m, 5H), 7.44 (t, 2H), 7.34 (m, 2H), 3.7 (m, 4H), 3.6 (t, 2H), 3.48 (s, 2H).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].O>C(O)C>[CH2:1]([NH:4][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCNC(C)C(=O)OC
Yield: 60.1 %

Procedure:
To a mixture of 10 g (0.18 mole) of allylamine, 10.8 g (0.2 mole) of sodium bicarbonate in 50 ml of ethanol is added 30 g (0.18 mole) of methyl 2-bromopropionate dropwise. The resulting mixture is heated under reflux for 5 hours. The reaction mixture is cooled, poured into water, and extracted with ether. The combined ether extracts are washed with water and dried over magnesium sulfate. The drying agent is filtered and the filtrate is concentrated under reduced pressure to give 15.5 g of a light yellow oil. This material is further purified by distillation to give 10.5 g of pure product.