Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH3:9])[CH2:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.CCN(CC)CC>C1COCC1>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][CH:2]([CH3:9])[CH2:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: CC(N)CNS(C)(=O)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Reaction time: 0.08 h
Yield: 85.3 %

Procedure:
N-(2-Amino-propyl)-methanesulfonamide (325 mg, 2.14 mmol, 1.5 eq.) in THF (20 mL) was cooled to 0 C and 2,4,5-trichloropyrimidine (261 mg, 1.43 mmol, 162 μL, 1.0 eq.) was added. The reaction was stirred for 5 minutes and then NEt3 (711 mg, 7.04 mmol, 516 μL, 4.9 eq) was added. After 5 minutes, external cooling was removed and the reaction was stirred under a nitrogen atmosphere for 3 hours. The reaction was then partitioned between CH2Cl2 (30 mL) and sat. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (15 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure onto silica gel. Purification by silica gel chromatography (dry loaded) using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-propyl]-methanesulfonamide as a white solid (365 mg, 85%). m.p.=160° C.; LCMS (m/e) 299 (M+1); 1H-NMR (d6-DMSO, 400 MHz) δ 8.18 (s, 1H), 7.59-7.50 (m, 1H), 7.26-7.15 (m, 1H), 4.36-4.22 (m, 1H), 3.21-3.05 (m, 2H), 2.91 (s, 3H), 1.18 (d, 3H, J=6.6 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([P:13]([OH:16])(=[O:15])[OH:14])[P:9]([OH:12])(=[O:11])[OH:10].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>>[C:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([P:13]([OH:16])(=[O:14])[OH:15])[P:9]([OH:10])(=[O:12])[OH:11])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: O=P(O)(O)C(CCCCCCO)P(=O)(O)O
Product: C=C(C)C(=O)OCCCCCCC(P(=O)(O)O)P(=O)(O)O

Procedure:
Following the General Synthetic Procedure B, methyl 6-chlorohexanoate is reacted with tetramethyl methanebisphosphonate to produce tetramethyl 5-methoxycarbonylpentyl-methanebisphosphonate that is then hydrolyzed to yield 5-carboxypentyl-methanebisphosphonic acid, and then hydrogenated to reduce the carboxy group to a hydroxymethylene group. The resulting 6-hydroxyhexyl-methanebisphosphonic acid is then methacrylated with methacryloyl chloride to afford 6-methacryloxyhexyl-methanebisphosphonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[O:22].ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N+:11]([O-:40])=[CH:10][C:9]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c2ncc(NC(=O)Nc3ccc(F)cc3F)c(-c3ccccc3Cl)c2c1
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)c(-c1ccccc1Cl)c(NC(=O)Nc1ccc(F)cc1F)c[n+]2[O-]

Procedure:
A mixture of 4-(2-chlorophenyl)-3-[3-(2,4-difluoro-phenyl)ureido]- 6,8-dimethylquinoline (1.1 g), m-chloroperbenzoic acid (1.08 g) and dichloromethane (15 ml) was refluxed for 20 hrs. The reaction mixture was washed with aqueous sodium sulfite solution, aqueous sodium hydrogen carbonate solution and water, successively. After being dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was recrystallized from a mixture of methanol and chloroform to give 4-(2-chlorophenyl)-3-[3-(2,4-difluorophenyl)ureido]-6,8-dimethylquinoline 1-oxide as pale yellow prisms. Yield 0.72 g (63.2%). m.p. 230°-232° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](=O)[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[CH2:1]([N:4]([CH2:12][C:13](=[N:22][OH:23])[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)c1cnccn1)C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=CCN(CC(=NO)c1cnccn1)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
tert-Butyl N-allyl-N-(2-oxo-2-pyrazin-2-yl-ethyl)carbamate (6.53 g, 23.55 mmol) is dissolved in ethanol (22 mL) with stirring under nitrogen. Hydroxylamine hydrochloride (3.80 g, 54.16 mmol) and pyridine (2.67 mL, 32.97 mmol) are added and the resulting solution is heated at 80° C. under nitrogen for 80 minutes. The reaction is then cooled to room temperature and is concentrated to a small volume under reduced pressure. Dichloromethane (200 ml) and 1 M aqueous sodium hydroxide (60 ml) are added and the phases are separated. The aqueous phase is re-extracted with dichloromethane (2×200 mL). The combined organic extracts are dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The crude product is purified by silica gel chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound as a mixture of E/Z isomers (6.61 g, 96%). ES/MS (m/e): 293 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@H:3]1O.[CH3:34][N:35]=[C:36]=[S:37]>>[CH3:34][NH:35][C:36]1[S:37][C@H:3]2[CH2:4][C@H:5]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:6]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:2]2[N:1]=1
Reactant: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1O
Reactant: CN=C=S
Product: CNC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)C[C@@H]2S1

Procedure:
The title compound was prepared via a synthetic sequence as described above Intermediate Example 7, starting form (1R,2S,3R,4R,5R)-2-amino-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)cyclohexanol (0.150 g, 0.336 mmol) and methyl isothiocyanate (MeNCS) (0.049 g, 0.67 mmol). The crude product was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:20 to 1:3), affording (3aR,4R,5R,6R,7aS)-2-(mthylamino)-4,5-bisbenzyloxy-6-(benzyloxymethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]thiazole as a colorless oil (0.16 g, impure).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:16][CH:15]1[CH2:17][C:10]2[C:8]3[C:9]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]=3[CH:13]=[CH:12][C:11]=2[C:14]1=[O:18]
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2c(ccc3sc4ccccc4c23)C1=O
Reaction time: 8 h

Procedure:
20 g (108.7 mmol) of dibenzothiophene (1) were added at −78° C. to an agitated solution of 10.6 ml methacryloyl chloride (108.7 mmol) and 15.3 g AlCl3 (114.8 mmol) in 250 ml methylene chloride and brought to room temperature overnight. The solution was hydrolysed carefully at 0° C., the organic phase was separated, washed with an aqueous solution of K2CO3 and dried over Na2SO4. After removal of the solvent and crystallisation in toluene/pentane≈10:1, 2-methyl-1,2-dihydrobenzo[b]indeno[4,5-d]thiophen-3-one (2) was obtained as crystalline solid material (21.6 g, 85.9 mmol, 79%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[C:10]3[C:14]([O:18][CH2:19][CH2:20][CH2:21]Cl)=[CH:15][CH:16]=[CH:17][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:28][C:27](=[O:36])[N:26]([CH3:37])[C:25]1=[O:38].C(N(CC)CC)C>CN(C)C=O.[Br-].C([N+](CC)(CC)CC)C>[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][O:18][C:14]3[C:10]4[C:11](=[O:13])[CH2:12][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:8][C:9]=4[CH:17]=[CH:16][CH:15]=3)[CH2:32][CH2:31]2)=[CH:28][C:27](=[O:36])[N:26]([CH3:37])[C:25]1=[O:38]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: O=C1CC(c2ccccc2)Oc2cccc(OCCCCl)c21
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCCOc3cccc4c3C(=O)CC(c3ccccc3)O4)CC2)cc(=O)n(C)c1=O

Procedure:
In 10 ml of N,N-dimethylformamide, reaction was carried out at 100° C. for 8 hours among 2.5 g of the previously obtained 2-phenyl-5-(3-chloropropoxy)-4-oxo-2,3-dihydro-4H-1-benzopyran (Compound 20), 1.2 g of 1,3-dimethyl-6-(piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (Compound 3), 1.0 g of tetraethylammonium bromide and 2.0 ml of triethylamine. The resultant reaction solution was concentrated under reduced pressure, and the residue was then dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and then purified through a silica gel column chromatograph (chloroform:methanol=40:1 in volume ratio), thereby obtaining 0.80 g of 1,3-dimethyl-6-(4-[3-(2-phenyl-4-oxo-2,3-dihydro-4H-1-benzopyran-5-yl)oxypropyl]piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (the non-oxalate of Compound 21).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>O>[CH3:6][NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH3:23])=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: CCOc1ccc(N2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(N2CCC(CNC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
[1-(4-Ethoxy-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (963 mg, 2.88 mmol, prepared in accordance with Example 106) is added to a molar solution of lithium aluminium hydride in tetrahydrofuran (10 mL, 10 mmol) and the resulting mixture is refluxed for 2 hours. After cooling with an ice bath, water (1 mL) is added carefully and the mixture is stirred overnight at room temperature. The reaction is then filtered and the filtrate is concentrated under reduced pressure. The residue obtained is dried under high vacuum to afford the desired product (701 mg; 2.83 mmol).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23].[OH:25][C:26]1[C:27]([CH3:40])=[C:28]([C:31]([O:36][CH2:37][CH2:38][OH:39])=[C:32]([CH3:35])[C:33]=1[CH3:34])[CH2:29][Cl:30]>CN(C)C=O>[ClH:30].[OH:25][C:26]1[C:27]([CH3:40])=[C:28]([C:31]([O:36][CH2:37][CH2:38][OH:39])=[C:32]([CH3:35])[C:33]=1[CH3:34])[CH2:29][N:10]([CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23])[CH3:9]
Reactant: Cc1c(C)c(OCCO)c(CCl)c(C)c1O
Reactant: CNCCOc1cc(C)c(O)cc1C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(OCCN(C)Cc2c(C)c(O)c(C)c(C)c2OCCO)c(C(C)C)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
Triethylamine (2.8 ml) was added dropwise to a solution of N-methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hydrochloride (2.60 g) and 3-hydroxy-6-(2-hydroxyethoxy)-2,4,5-trimethylbenzyl chloride (2.45 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was poured on ice water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 3.8 g of a pale brown oil. The oil was dissolved in a small amount of methanol and conc. hydrochloric acid (1.2 ml) was added. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol-diethyl ether to give 2.9 g of the title compound (colorless crystals).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:5])[CH3:2].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C)c[nH]c1CCNCCN(C)C
Reaction time: 1 h
Yield: 112.2 %

Procedure:
A stirred solution of 2-[(2-dimethylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (281 mg, 1 mmol) in anhydrous tetrahydrofuran (2 ml) was added dropwise slowly with 1M borane-tetrahydrofuran complex in tetrahydrofuran (3 ml, 3 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was stirred for 1 hour and heated to reflux for another 5 hours. The mixture was added with cold water (5 ml) and 1N hydrochloric acid (2 ml) and stirred for 5 minutes. The resulting solution was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[2-(2-dimethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (300 mg) as a brown oil which was used as such.
Reaction SMILES: OC1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[O:12]1[CH2:16][CH2:15][O:14][C:13]1=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:12][CH2:16][CH2:15][O:14][C:13]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(O)cc(C=O)c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OCCO)c1
Temperature: 110 °C

Procedure:
3-Hydroxy-5-methoxy-benzaldehyde (12.0 g, 78.9 mmol) and [1,3]dioxolan-2-one (13.9 g, 157.0 mmol) in anhydrous DMF (50 mL) was added potassium carbonate (21.6 g, 157.0 mmol). The mixture was then heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature. Solid potassium carbonate was filtered and washed with ethyl acetate. The organic phase was collected and solvent was removed. The residue was purified by column chromatography (silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate 7:1), to give 3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde as a brown liquid. Yield: 10.0 g (65%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=O)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (93 mg, 71%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[C:18]([OH:26])([CH3:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.[Cl-].[Na+].O>[CH2:27]([O:26][C:18]([C:5]1[CH:6]=[CH:7][C:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:9][C:4]=1[Cl:3])([CH3:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cn1cncn1)(OCc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reaction time: 18 h
Yield: 68.9 %

Procedure:
Sodium hydride (0.04 g) was added to a solution of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol (0.5 g) in THF (15 mL). After 30 min benzylbromide (0.27 g) was added and the mixture was stirred for 18 h at reflux. Brine was added and the mixture was extracted with dichloro methane (3×). The combined organic phases were dried, filtered through a silica plug and evaporated. The crude product was purified by column chromatography to yield 0.43 g of the desired compound.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[C:22]1([NH:32][C:33](=[O:44])[O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][CH:37]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>ClCCl.C(OCC)C>[C:22]1([NH:32][C:33](=[O:44])[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([CH:42]=[O:43])=[CH:40][CH:41]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1cccc2ccccc12)OCc1ccc(CO)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc(COC(=O)Nc2cccc3ccccc23)cc1
Reaction time: 5 h
Yield: 85.7 %

Procedure:
PDC (2.1 g, 5.6 mmol) was added to a stirred mixture of alcohol 7 (1.72 g, 5.6 mmol) and activated 4 Å molecular sieves (1.0 g) in anhydrous dichloromethane (20 mL). The resulting mixture was stirred for 5 h; then it was diluted with diethyl ether (20 mL). The resulting suspension was filtrated through a pad of silica gel. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (hexanes/ethyl acetate=5:1) to provide aldehyde 6 (1.46 g, 4.8 mmol) as a white solid in 85% yield: m.p.: 153-154° C.; IR (thin film): 3272, 1691, 1609, 1544, 1504, 1257, 1206 cm−1; 1H NMR (500 MHz, CDCl3): δ 10.01 (s, 1H), 7.93-7.81 (m, 5H), 7.68 (d, J=8.2 Hz, 1H), 7.57 (s, 1H), 7.55-7.40 (m, 4H), 5.32 (s, 2H) ppm; 13C NMR (101 MHz, CDCl3): δ 192.07, 192.03, 154.26, 143.05, 136.09, 134.16, 132.34, 130.94, 130.08, 128.82, 128.28, 126.74, 126.41, 126.20, 125.83, 125.47, 120.68, 119.36, 66.35 ppm. HRMS (m/z): [M+Na]+ calcd. for C19H15NNaO3, 328.0944; found, 328.0938.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17](Br)[C:16]([CH3:20])=[CH:15][C:14]=2[C:21]#[N:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]([CH3:20])=[CH:15][C:14]=2[C:21]#[N:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C#N)c(OC2CN(C(=O)OC(C)(C)C)C2)cc1Br
Reactant: OB(O)c1ccccc1
Product: Cc1cc(C#N)c(OC2CN(C(=O)OC(C)(C)C)C2)cc1-c1ccccc1

Procedure:
Prepared from the title compound of Step A as described in Example 1 Step E using phenylboronic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[C:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8](/[CH:9]=[CH:15]/[C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1cccc(-c2cccs2)c1
Product: O=C(O)c1ccc(C(=O)/C=C/c2cccc(-c3cccs3)c2)cc1
Yield: 71 %

Procedure:
The title compound was prepared by condensing 3-(thiophen-2-yl)-benzaldehyde (Ex-42A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 238° C. (dec), 71% yield. 1H-NMR (DMSO-D6) δ 13.40 (bs, 1H), 8.29 (d, J=8 Hz, 2H), 8.22 (s, 1H), 8.13 (d, J=8 Hz, 2H), 8.04 (s, 1H), 7.87 (s, 1H), 7.83 (d, J=8 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.69 (d, J=4 Hz, 1H), 7.63 (d, J=5 Hz, 1H), 7.52 (t, J=8 Hz, 1H), 7,20 (dd, J=4, 5 Hz, 1H). HRMS m/z=calc. 335.0742, found 335.0749.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCOc1ccc(CC(=O)OCC)cc1
Yield: 83.1 %

Procedure:
The ethyl 4-hydroxyphenylacetate (59 g) and sodium ethoxide (22.4 g) are dissolved in ethanol (150 ml) and thereto is added n-octyl bromide (63.5 g), and the mixture is refluxed for 3 hours and concentrated under reduced pressure, and thereto is added ethyl acetate to dissolve the oily substance. The mixture is washed with water, dried over anhydrous magnesium sulfate, distilled under reduced pressure to remove ethyl acetate, and further distilled under reduced pressure to give ethyl 4-n-octyloxyphenylacetate (79.6 g, b.p. 179° C./0.1 mmHg).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:21])[C:3]=1[CH:22]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:31][C:32]#[N:33])C=CC=CC=1>C(#N)C>[NH2:33][C:32]1[CH:31]=[CH:22][C:3]2[C:4](=[O:21])[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6](=[O:14])[N:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]=2[N:1]=1
Reactant: Nc1c(C=O)c(=O)n(-c2ccccc2)c(=O)n1-c1ccccc1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: Nc1ccc2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c2n1
Yield: 44.6 %

Procedure:
A solution of 6-amino-5-formyl-1,3-diphenyluracil (5.0 g, 16.3 mmol) and 2-(triphenylphosphoranylidene)acetonitrile (5.9 g, 19.6 mmol) in anhydrous acetonitrile (100 mL) was heated to reflux for 24 hours in an argon stream. The reaction mixture was allowed to cool and the solvent was evaporated therefrom in vacuo. The crude crystals separated out therefrom were recrystallized from benzene to give 7-amino-1,2,3,4-tetrahydro-1,3-diphenylpyrido[2,3-d]pyrimidine-2,4-dione (2.4 g) in a 45% yield.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:28])[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1)[CH3:30]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNCC
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI/CI): predicted mass C23H23N5O2, 401.2.