Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])#[N:2].C(NCC)C.[SH2:20]>>[CH2:13]([O:12][Si:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[CH2:4][CH2:3][C:1]([NH2:2])=[S:20])[CH3:14]
Reactant: CCO[Si](CCC#N)(OCC)OCC
Reactant: S
Solvent: CCNCC
Product: CCO[Si](CCC(N)=S)(OCC)OCC
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Utilizing a 15 gallon high pressure stainless steel system, 80 pounds of beta-cyanoethyltriethoxysilane and 8 pounds of diethylamine were added initially. With a diptube, 12 pounds of hydrogen sulfide was charged into the reactor while cooling was maintained. The reactor was then heated to 60° C. with stirring for 6 hours. The residual hydrogen sulfide (80 psig) was carefully vented into a caustic scrubber and the product thioamide (94 pounds) was collected. The product, analyzed by InfraRed Spectroscopy, contained 5% unreacted nitrile.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.[C:17]([O:25]C)(=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>C(O)(C)(C)C>[C:20]([C:19](=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH3:7])[CH:10]=1)[CH2:18][C:17]([OH:25])=[O:24])([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CCC(=O)OC
Reactant: COc1cccc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=Cc1cccc(OC)c1)CC(=O)O

Procedure:
To a refluxing suspension of 15.71 g (140 mmol, 1.4 eq) of potassium t-butoxide in 50 ml of t-butylalcohol is dropped in a mixture of 12.17 (100 mmol) of 3-methoxybenzaldehyde and 15.70 ml (120 mmol, 1.2 eq) of dimethyl succinate dissolved in 20 ml of t-butylalcohol. The mixture is refluxed for 3 hours, concentrated in vacuo, acidified to pH ~1 using 1N HCl, and extracted with ethylacetate. The organics are dried (MgSO4) and concentrated in vacuo to give 3-carbomethoxy-4-(3-methoxyphenyl)-3-butenoic acid in the form of a yellow oil which is used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[C:17](/[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)=[CH:7]\[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)#[N:18]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: N#Cc1ccc(C=O)cc1
Product: COc1ccc(/C(C#N)=C/c2ccc(C#N)cc2)cc1OC
Yield: 112.9 %

Procedure:
4-Cyanobenzaldehyde (1.97 g) and 3,4-dimethoxybenzyl cyanide (1.80 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (3.33 g, yield: 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:14][C:15]1[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>>[Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:7]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[C:15]([CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=3)[CH2:23][CH2:24]2)=[O:9])[CH:10]=1
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: COc1cc(I)c(Cl)cc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 96.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 67 and using 5-chloro-4-iodo-2-methoxybenzoic acid (1 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (612 mg) described in Preparation Example 47, the title compound (1.5 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:8][S:7][C:6]=2[CH:23]=1.I.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](SC)=[NH:31].C([O-])(O)=O.[Na+]>C(O)C>[CH3:22][N:14]([CH2:13][CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][S:7][C:6]2[CH:23]=[C:2]([NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[NH:31])[CH:3]=[CH:4][C:5]1=2)[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: CN(CCCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
A solution of tert-butyl 3-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)propyl(methyl)carbamate (0.52 g, 1.541 mmol) in dry ethanol (20 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.879 g, 3.08 mmol) at room temperature and stirred over night (18 hours). The reaction was basified with saturated NaHCO3 solution (50 mL), and the product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (2:98 (2 M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title product (0.60 g, 87%) as a solid. ESI-MS (m/z, %): 447 (MH+, 100).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+].[NH3:29]>O>[NH2:29][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
79.5 g of 1,4-dihydroxyanthraquinone, 210 ml of water, 5.6 g of sodium dithionite, 60 g of 50% strength by weight sodium hydroxide solution and 240 g of 25% strength by weight ammonia solution were introduced into a pressure-resistant apparatus. The apparatus was then sealed pressure-tight and its contents were heated to 100° C., giving rise to an autogenous pressure of 2.5 bar. The reaction mixture was held under these conditions for 3 h, then cooled down and depressurized. The precipitate found was filtered off with suction, washed salt-free with water and dried to leave 74.9 g of 1-amino-4-hydroxyanthraquinone (purity according to GC: 90.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH2:44]>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH:44][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: NCC1OCCO1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3OCCO3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and C-[1,3]dioxolan-2-yl-methylamine according to conditions described in general procedure C. Mp: 96-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.57-1.61 (m, 6 H), 3.27-3.30 (m, 4 H), 3.60-3.89 (m, 6 H), 4.70-4.89 (bd, 1 H), 6.20-6.34 (bd, 1 H), 6.94-6.99 (m, 1 H), 7.14-7.21 (m, 2 H), 7.40 (d, J=8.0 Hz, 1 H), 7.44 (s, 1 H), 7.52-7.61 (m, 3 H), 7.81 (d, J=7.3 Hz, 1 H), 7.96-7.98 (m, 1 H), 8.21 (s, 1 H), 10.42 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([O:24][CH2:25][CH:26]2[O:28][CH2:27]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.Cl>C(O)(C)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH:26]([OH:28])[CH2:25][O:24][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Agent: Cl
Solvent: CC(C)O
Product: Oc1ccccc1N1CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
4.56 g. (0.025 mole) 1-(2-hydroxyphenyl)-piperazine and 5.6 g. (0.028 mole) 2,3-epoxypropyl naphthyl ether are dissolved in 50 ml. isopropanol and the solution obtained is heated under reflux for 5 hours, while stirring. Thereafter, the reaction mixture is diluted with a further 50 ml. isopropanol and acidified isopropanolic hydrochloric acid. A voluminous product precipitates out which is filtered off with suction, washed several times with isopropanol and recrystallised from methanol. Yield 8.8 g. (77% of theory); m.p. 249°-250° C.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:19][C:20]1[C:21]([OH:30])=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24].[N:31]1([C:37]2[N:38]=[C:39]([CH2:44][C:45]([O-])=[O:46])[NH:40][C:41](=[O:43])[CH:42]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Na+]>CN(C)C=O>[OH:30][C:21]1[C:20]([NH:19][C:45](=[O:46])[CH2:44][C:39]2[NH:40][C:41](=[O:43])[CH:42]=[C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:38]=2)=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COC(=O)c1cccc(N)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.4 %

Procedure:
6 ml of pyridine, 1g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 1 g of methyl 3-amino-2-hydroxybenzoate are added to a solution of 1 g of [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 6 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 1.27 g of methyl 2-hydroxy-3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.C(O)=O.C([NH2:16])=O.Cl>C(O)C>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([NH2:16])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: NC=O
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: CC(N)c1cccc(Br)c1
Temperature: 220 °C

Procedure:
A mixture of commercially available 3-bromoacetophenone (30 g, 0.1508 mol), formic acid (47 ml) and formamide (70 ml) was heated to 220° C. for 5 h. The brown liquid obtained was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated to provide a brown liquid. Ethanol (375 ml) and conc.HCl (75 ml) were added to the brown liquid and the reaction mixture refluxed over night. Ethanol was removed completely under reduced pressure and the aqueous layer was washed with ether and ethyl acetate to remove all non-basic impurities. The aqueous layer was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, and concentrated to provide 26 g (86.65%) of A1.13a This compound was taken to the next step with out further purification. 1H NMR (CDCl3, 300 MHz) δ 1.38 (d, 3H), 4.1 (q, 1H), 7.2 (m, 1H), 7.27 (m, 1H), 7.37 (m, 1H), 7.51 (s, 1H). LS-MS (M−H)+=200.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15]>ClCCl>[N:1]1([S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCOCC1
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of morpholine (1.91 g, 22 mmol and triethylamine (2.2 g, 22 mmol) in dichloromethane (100 mL) at 0° C. was added 2-nitrobenzenesulfonyl chloride (4.42 g, 20 mmol). The mixture was stirred for 4 h and then additional dichloromethane (100 mL) was added. The dichloromethane solution was washed with saturated NaHCO3 (2×50 mL), 10% HCl (2×50 mL) and brine (50 mL) and dried over Na2SO4. Evaporating the solvent in vacuo gave the title compound as a yellow solid (5.3 g, 97%). 1H-NMR (300 MHz, CDCl3) δ7.97 (d, J=7.3 Hz, 1H), 7.62-7.77 (m, 3H), 3.75 (t, J=4.7 Hz, 4H), 3.30 (t, J=4.8 Hz, 4H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:5]1[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1cc(C(F)(F)F)cn1
Yield: 24 %

Procedure:
The title compound was prepared according to the method described for Preparation 75 using 4-(trifluoromethyl)-1H-pyrazole and tert butyl bromoacetate to afford the title compound as a yellow solid (24%, 1.32 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20]O.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:22]([CH:19]1[CH2:20][N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:18]1)[CH2:23][CH3:24]
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCCC(N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCC1CN2N=C(c3cccc(C(F)(F)F)c3)C=CC2=N1
Temperature: 130 °C

Procedure:
A mixture of 5.0 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 10 g of 2-amino-1-pentanol is heated at 130° C. for 24 hours, cooled, poured into water and extracted with dichloromethane. As for Example 3, the obtained product is reacted with thionyl chloride and the ring is closed with potassium carbonate in ethanol to give 2,3-dihydro-2-propyl-6-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([N+:22]([O-])=O)[CH:15]=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[Cl-].[NH4+].C1C[O:30]CC1>CO.O.[Fe]>[NH2:22][C:16]1[CH:15]=[C:14]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]3[C:10]([CH:11]([CH3:13])[CH3:12])=[N:9]2)[CH:21]=[CH:20][C:17]=1[C:18]([NH2:19])=[O:30]
Reactant: C1CCOC1
Reactant: CC(C)c1nn(-c2ccc(C#N)c([N+](=O)[O-])c2)c2nccc(Cl)c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(N)c2)c2nccc(Cl)c12
Temperature: 70 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Compound (6b) (0.335 g) was dissolved in DMF (8.6 mL), and sodium hydride (0.097 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 4-fluoro-2-nitrobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration and washed by sprinkling water to obtain 4-{4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.5 g, 85%). 4-{4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.35 g) and ammonium chloride (0.35 g) were dissolved in a solvent mixture of THF (3 mL), methanol (3 mL), and water (3 mL). Iron (0.57 g) was added to the resulting solution, followed by stirring at 70° C. for 1 hr. Insoluble matters were filtered by celite, and the solvent was distilled away. The precipitate was washed with water and was collected by filtration to obtain compound (106a) (0.32 g, 95%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].N12CCCN=C1CCCCC2.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Reactant: C=CC(=O)OC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1.0 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, 0.28 ml of 1,8-diazabicyclo[5.4.0]-undec-7-ene, 0.34 ml of methyl acrylate and 10 ml of N,N-dimethylformamide was stirred at room temperature for 12 hours. Then, the solvent was distilled off under reduced pressure, after which the resulting residue was added to a mixed solvent of 30 ml of ethyl acetate and 30 ml of water, and the pH was adjusted to 3 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with three 30-ml portions of ethyl acetate. The combined organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform : methanol=20:1) to obtain 0.68 g of methyl 3-[4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]propionate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[CH2:9](O)[CH2:10][OH:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[N:6]=1
Reactant: O=Cc1csc(Br)n1
Reactant: OCCO
Solvent: Cc1ccccc1
Product: Brc1nc(C2OCCO2)cs1
Yield: 74.7 %

Procedure:
2-Bromothiazole-4-carbaldehyde (6.56 g, 34.17 mmol) [A. T. Ung, S. G. Pyne/Tetrahedron: Asymmetry 9 (1998) 1395-1407]and ethylene glycol (5.72 ml, 102.5 mmol) were heated under reflux in toluene (50 ml),with a Dean and Stark trap fitted, for 18 hr. The product was concentrated and purified by column chromatography (15% ethyl acetate/hexane) to give the product as a yellow solid (6.03 g); m/z 236,238.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Yield: 100.4 %

Procedure:
To a solution of 2-chloro-5-(trifluoromethyl)benzoic acid (15 g, 66.8 mmol) in methylene chloride (200 mL) was added oxalyl chloride (12.7 g, 100 mmol) drop wise followed by the addition of 5-6 drops of DMF. The reaction mixture was concentrated, the residue partitioned between methylene chloride and 5% aq. sodium carbonate. The organic layer was dried (MgSO4) and concentrated to give the title compound as a pale oil (16 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:21])=O>C(OCC)(=O)C>[Cl:21][C:3]1[N:2]([CH3:1])[C:6]2[C:7]([CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: CCCC(CCC)c1cccc2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCC(CCC)c1cccc2nc(Cl)n(C)c12
Temperature: 100 °C
Yield: 86 %

Procedure:
The crude 1-methyl-7-(1-propylbutyl)-1,3-dihydrobenzimidazol-2-one (710 mg, 2.88 mmol) was dissolved in 10 mL of phosphorous oxychloride and heated at 100° C. overnight. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue thus obtained was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give 655 mg (86%) of the title compound, which was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[N:59]=[C:58]([NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:66])[CH3:65])[CH:57]=[C:56]([N:67]3[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]3)[N:55]=2)=[CH:50][CH:49]=1>CN1C(=O)CCC1>[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([C:54]2[N:59]=[C:58]([NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:66])[CH3:65])[CH:57]=[C:56]([N:67]3[CH2:72][CH2:71][N:70]([C:1]([C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)=[O:13])[CH2:69][CH2:68]3)[N:55]=2)=[CH:52][CH:53]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(=O)NCCNc1cc(N2CCNCC2)nc(-c2ccc(Cl)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)NCCNc1cc(N2CCN(C(=O)c3ccc4ccccc4n3)CC2)nc(-c2ccc(Cl)cc2)n1
Reaction time: 12 h

Procedure:
A solution of quinaldic acid (60 μl of a 0.3M solution in NMP), HATU (60 μl of a 0.3M solution in NMP) and diisopropylethylamine (60 μl of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 5 min. N-(2-{[2-(4-chlorophenyl)-6-piperazin-1-ylpyrimidin-4-yl]amino}ethyl)acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 12 hr. Purification via ion exchange silica (SCX) yields the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1>[C:25]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(S)-benzyloxazolidin-2-one (56 mmol) (Aldrich, Milwaukee, Wis.) in THF at −78° C. was added 2.5 M n-BuLi in hexane (22.4 mL, 56 mmol) and the reaction stirred at −78° C. for 2 hr. To this was added via cannula a −78° C. solution of hexanoyl chloride (65 mmol) in THF and the mixture stirred at −78° C. for 2 hr, then allowed to warm to room temperature and stirred overnight. The reaction was then quenched with aqueous saturated NH4Cl, extracted with ethyl acetate, dried, and purified by silica gel chromatography (hexanes/ethyl acetate) to afford N-hexanoyl-4-(S)-benzyloxazolidin-2-one J-1.
Reaction SMILES: [OH-].[K+].OC[C:5]12[CH2:12][O:11][C:8]([CH3:13])([O:9][CH2:10]1)[O:7][CH2:6]2.[CH3:14][O:15]CBr>CS(C)=O.O>[CH3:14][O:15][C:5]12[CH2:6][O:7][C:8]([CH3:13])([O:9][CH2:10]1)[O:11][CH2:12]2
Reactant: COCBr
Reactant: CC12OCC(CO)(CO1)CO2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC12COC(C)(OC1)OC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Powdered potassium hydroxide (16.2 g, 0.290 mol) is suspended in 100 mL of dimethyl sulfoxide and the mixture is stirred at 25° C. for 5 min. Then 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.21octane (10.0 g, 0.062 mol) is added followed by bromomethyl methyl ether (9.3 g, 6.1 mL, 0.074 mol). The reaction mixture is stirred for 30 min and then diluted with water (1 L) and extracted with dichloromethane several times. The combined organic layers are washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4-(methoxy)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane. This crude material is dissolved in methanol (100 mL) and stirred with pyridinium p-toluenesulfonate (1.6 g, 6.200 mmol) in water (100 mL) for 30 min. The pH of the solution is adjusted to 7 with solid sodium bicarbonate and the solvents are removed under reduced pressure. The resulting solids are triturated with methanol and the methanol solution is evaporated to give 2-(methoxymethoxy)-1,1,1-tris(hydroxymethyl)ethane.