Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[OH-].[Na+].[C:11]1([CH:17]([N:24]=[C:25]=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>>[CH:17]([NH:24][C:25]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])=[O:26])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCCS(=O)(=O)O
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCCS(=O)(=O)O)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The 3-amino-1-propanesulfonic acid (1.0 g, 7.2 mmol) was dissolved in 3N NaOH (370 mg, 9.4 mmol in 3 mL of water). After the solution was cooled to 0° C., diphenylmethyl isocyanate (1.4 mL, 7.2 mmol) was added. The reaction mixture was allowed to warm up to room temperature, stirred for 8 h (r.t.), and followed by addition of 3N NaOH (3 mL). The reaction mixture was stirred for 18 h. The pH of the reaction mixture was brought to 3 with 5N HCl. The solvent was evaporated under reduced pressure. EtOH (15 mL) was added and the mixture was stirred at reflux for 30 sec. The hot mixture was filtered. The filtrate was evaporated to dryness. This process was repeated 2 more times. The final product was dried in vacuo, affording compound AF, 837 mg (34%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:7]1=[O:17].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[O:17]=[C:7]1[C:8]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH2:10][CH2:11][NH:6]1
Reactant: COc1ccc(CN2CCC=C(CCC(=O)O)C2=O)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC1=CCCNC1=O
Temperature: 80 °C
Yield: 49.1 %

Procedure:
50 mg of 3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid (0.157 mM) was dissolved in 1 ml of trifluoroacetic acid solution. Then 0.074 ml of triethyl silane (0.465 mmol) was added thereto and the mixture was heated for 20 min at 80° C. The solvent was removed in vacuo and the remaining residue was recrystallized with mixture solution of methanol and ethylacetate to give 13 mg of 3-(2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid (g) (yield: 50%).
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:12]([NH:14][C@H:15]([C:25](OC)=[O:26])[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:37][NH2:38]>CN(C=O)C>[NH:1]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[C@H:2]([C:12]([NH:14][C@H:15]([C:25]([NH:37][NH2:38])=[O:26])[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)NN
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
The substance [28] (191 g, 0.393 M) was dissolved in DMF (500 ml). Hydrazine hydrate (100%) (200 ml) was added dropwise and stirred at room temperature for three hours. The DMF was removed in vacuo and water was added thereto. The thus-formed precipitate was filtered, dried, and recrystallized twice from ethyl acetate-hexane to obtain the substance [29] (183.6 g, yield: 96.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)#[CH:26].CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:26]#[C:25][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#Cc1ccccn1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#Cc3ccccn3)cc2c1O
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A solution of the title compound of Example 5 (540.3 mg), 2-ethynyl pyridine (0.172 g), PdCl2 (PPh3)2 (21.1 mg), and 0.75 mL Et3N in 3 mL DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and diluted with H2O. A tan solid precipitates, which is collected, dissolved in a mixture of CH2Cl2 and MeOH, and adsorbed onto silica. The crude product is chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized from hot MeOH/CH2Cl2 and hexanes to yield 0.302 g of the desired product as a white solid.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1>C(O)C>[C:2]([NH:3][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[S:14])#[N:1]
Reactant: N#CN
Reactant: Fc1ccc(N=C=S)cc1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
The suspension of monosodium cyanamide (2.1 g, 32.6 mmol) in absolute ethanol (50 mL) was slowly treated with 4-fluorophenylisothiocyanate (5.0 g, 32.6 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (4.1 g), m.p. >270° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][SH:9].[CH3:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14]>[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:8]([S:9][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CC(=O)OC
Reactant: CCCCCCCCS
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: CCCCCCCCSCCC(=O)OC
Reaction time: 3 h
Yield: 143.6 %

Procedure:
Into the same type of equipment used in Example 1, 146 grams of 1-octylthiol was added over a 40 minute period with stirring to 0.7 grams of benzyl trimethyl ammonium hydroxide and 180.6 grams of methylacrylate. Over the 1/2 hour period, the temperature of the reaction went from 25° C. to 60° C. The reaction was stirred an extra 3.0 hours wherein the temperature went from 60° C. to 28° C. The reaction mixture was stripped at 102° C. and 15 mm pressure. 333 grams of product was obtained having a purity of approximately 96.4% as measured by GC analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:5]#[N:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:15]1[C:14]2[C:2]3[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=3[O:10][CH2:11][CH2:12][C:13]=2[CH:17]=[CH:16]1
Reactant: N#Cc1ccc(OCCc2ccsc2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)-c1sccc1CCO2
Temperature: 90 °C

Procedure:
To a solution of 3-bromo-4-(2-thiophen-3-yl-ethoxy)-benzonitrile (4.50 g) in DMF (20 mL) was added palladium acetate (327 mg), triphenylphosphine (766 mg) and potassium carbonate (4.03 g) and the reaction heated at 90° C. for 16 h. After cooling to room temperature the mixture was diluted with ethyl acetate (60 ml) and filtered. The filtrate was washed with brine (80 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[CH3:30][NH:31][NH2:32].O1CCCC1.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)=[O:8])=[C:6]([C:7]([N:31]([CH3:30])[NH2:32])=[O:27])[CH:28]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CNN
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)N(C)N)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A mixture of 0.44 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.05 g of methylhydrazine and 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours. After the reaction mixture was mixed with water and ethyl acetate, layers were separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.40 g of N-[4-chloro-2-(N-methylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([O:14]C)=[O:13])=[CH:5]2.[OH-].[K+].O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2
Reactant: COC(=O)c1cc2cc(Cl)ccc2cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(Cl)ccc2cn1
Temperature: 80 °C
Yield: 13.4 %

Procedure:
Methyl 6-chloro-isoquinoline3-carboxylate (0.80 g, 3.6 mmol) is suspended in 95% EtOH (35 mL). KOH (0.61 g, 10.9 mmol) is added, and the reaction is heated to 80° C. When a white precipitate begins to form, 10 mL of H2O is added and all solid is redissolved. After heating for 1 hour, the reaction is cooled to rt and a white precipitate forms. The precipitate (identified as the K+ salt) is collected by vacuum filtration. The filtrate is acidified with concentrated HCl until the pH is between 4 and 5. The filtrate is loaded directly onto a column of AGW-×2 resin (H+ form) and the column is rinsed with MeOH. The product is eluted with a solution of 5% TEA in MeOH. This solution is concentrated, evaporated from MeCN three times, and the resulting solid is recrystallized from EtOH/H2O. This material is purified by preparative achiral HPLC to yield 0.10 g (13%) of 6-chloroisoquinoline-3-carboxylic acid. HRMS (FAB) calculated for C10H6ClNO2+H+: 208.0165, found 208.0164.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].Cl.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: [O-][n+]1ccccc1Cl
Reactant: NCCCCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: [O-][n+]1ccccc1NCCCCCO

Procedure:
2-(5-hydroxypentylamino)pyridine N-oxide was prepared dissolving 2-chloropyridine N-oxide.HCl (18.07 mmol), 5-amino-1-pentanol (36.14 mmol), and NaHCO3 (90.36 mmol) in tert-amyl alcohol (20 mL), then refluxing overnight under Ar. After cooling, the reaction was filtered and concentrated to a green oil. Purification by silica gel chromatography (eluent: 94:5:1 CH2Cl2, MeOH, NH4OH) yielded a yellow solid (3.07 g). 1H NMR was consistent with the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C(=O)N(C)C)CC2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (6.4 mg, 0.059 mmol) was added to a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15.3 mg, 0.030 mmol) and triethylamine (12 μL, 0.089 mmol) in DCM (300 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (11.1 mg, 63.8%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.31 (d, J=6.3 Hz, 6H), 1.91-2.01 (m, 2H), 2.09-2.18 (m, 2H), 2.86 (t, J=5.7 Hz, 2H), 2.90 (s, 6H), 3.03-3.11 (m, 2H), 3.39-3.47 (m, 2H), 3.55 (t, J=5.7 Hz, 2H), 4.14 (quin, J=6.4 Hz, 1H), 4.27 (s, 2H), 4.49 (tt, J=7.3, 3.6 Hz, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 475.4.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10](Cl)=[N:11][C:12]([Cl:15])=[N:13][CH:14]=1.[CH3:17][O:18][CH2:19][C:20]([NH2:23])([CH3:22])[CH3:21].N1C=CC=NC=1>C(#N)C>[Br:8][C:9]1[C:10]([NH:23][C:20]([CH3:22])([CH3:21])[CH2:19][O:18][CH3:17])=[N:11][C:12]([Cl:15])=[N:13][CH:14]=1
Reactant: COCC(C)(C)N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: c1cncnc1
Product: COCC(C)(C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
Triethyl amine (73.1 mL, 526.6 mmol) was added slowly to a solution of 5-Bromo-2,4-dichloro-pyrimidine (40 g, 175.5 mmol) in acetonitrile (400 mL) at 00° C. and then 2-Methoxy-1,1-dimethyl-ethylamine (Preparation 255, 23.4 g, 263.3 mmol) was added to the mixture portion wise. The reaction mixture was stirred for another 16 hours at room temperature. TLC showed the presence of unreacted starting pyrimidine, but the reaction was not continued further. All the volatiles were removed in vacuo and the residue was taken in ethyl acetate, washed with water, brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified by column chromatography on silica gel (100-200 mesh, gradient of ethyl acetate:hexane 1:9 to 2:4) to afford the title compound as white solid in 23% yield (10 g of starting pyrimidine was recovered), 12 g.
Reaction SMILES: [Si](OC1C=C(C=CC=1)C([C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20](CC)CC)=[O:19])=[CH:16][CH:15]=1)O)(C(C)(C)C)(C)C.S(Cl)(Cl)=O.C[C@H]1CN[C@H](C)CN1.O.[F-].C([N+](CC)(CC)CC)C>>[C:18]([NH2:20])(=[O:19])[C:17]1[CH:25]=[CH:26][CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Agent: CC[N+](CC)(CC)CC
Agent: C[C@@H]1CN[C@@H](C)CN1
Agent: [F-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: NC(=O)c1ccccc1

Procedure:
4-(3-(tert-Butyldimethylsilyloxy)-α-hydroxybenzyl)-N,N-diethylbenzamide (Example 1, infra) was treated with thionyl chloride and trans-2,5-dimethylpiperazine as described in Example 5. The crude mixture of diastereomers was purified by chromatography on silica gel (Waters Prep 500) with dichloromethane:ethanol:triethylamine (100:0.25:0.1). The less mobile isomer (1.28 g, 2.5 mmol) was dissolved in acetonitrile and treated with tetraethylammonium fluoride hydrate (0.6 g, 4.0 mmol) as in Example 7 to give 0.46 g of (±)-N,N-diethyl-4-((αR*)-3-hydroxy-α-((2R*, 5S*)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide as a white solid, mp 175-177° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][NH2:13])[CH3:11].ClCCl>O1CCOCC1>[CH2:10]([O:12][N:13]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: CCON
Reactant: O=Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCON=Cc1ccc(O)cc1
Yield: 86 %

Procedure:
A solution of 4-hydroxybenzaldehyde (100 mg, 0.88 mmol) and 50% O-ethylhydroxylamine aqueous solution (0.6 ml, 4.9 mmol) in dioxane (2 ml) was stirred under an atmosphere of argon at room temperature for 16 hours and then heated at 90-100° for 3 hours when thin layer chromatography (silica, dichloromethane) indicated the reaction was complete. The solution was evaporated to dryness and the residue partitioned between ethyl acetate (20 ml) and water (5 ml). The organic layer was washed with water, dried (Na2SO4) and evaporated to afford 4-hydroxybenzaldehyde O-ethyloxime (125 mg, 92.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30](O)=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:40][CH2:41][CH2:42][NH:43][CH:44]([CH3:46])[CH3:45])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[Si](OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C>>[CH2:1]([O:8][C:9]1[C:10]([C:30]([N:43]([CH2:42][CH2:41][O:40][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:34])[CH3:35])[CH:44]([CH3:45])[CH3:46])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-((1-(3,4-dichlorophenyl)cyclo-pentyl)methyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (489) was synthesized from 5-(benzyloxy)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (488) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (245).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(N(C(C)C)CC)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:38][S:39]([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])(=[O:41])=[O:40]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-hydroxyethoxy]hexyl}-1,3-oxazolidin-2-one (200 mg) in dichloromethane (14 ml) under nitrogen at 0° was treated with diisopropylethylamine (0.10 ml) followed by methanesulfonyl chloride (0.04 ml). The mixture was stirred at 0° for 0.5 h and sat. sodium bicarbonate solution (30 ml) was then added. The mixture was extracted with dichloromethane (30 ml) and the organic extract dried (Na2SO4). The solvent was evaporated in vacuo to give the title compound (240 mg). LCMS RT=3.22 min, ES+ve 472 (MH)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(/C=C/c1cccc([N+](=O)[O-])c1)Nc1ccccc1C(=O)O

Procedure:
500 mg (1.53 mmol) of trans-3-nitrocinnamic acid-N-(2-methoxycarbonyl-phenyl)-amide are stirred into a mixture of 20 ml of methanol and 8 ml of 2N sodium hydroxide solution for two hours at 50° C. Then the methanol is distilled off in vacuo, the residue is diluted with about 150 ml of water and adjusted to about pH 2.5 with stirring. The product which is then precipitated is suction filtered, washed with about 10 ml of water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]1)[CH2:8]Br)[CH3:2].[P:23]([O:32]C(C)C)([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]1)[CH2:8][P:23]([O:28][CH:29]([CH3:31])[CH3:30])([O:24][CH:25]([CH3:27])[CH3:26])=[O:32])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)C1CCN(C(C)=O)CC1)NC=O
Product: CCOC(=O)C(C=C(CP(=O)(OC(C)C)OC(C)C)C1CCN(C(C)=O)CC1)NC=O
Reaction time: 18 h

Procedure:
2.68 g (7.14 mmol) of 4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester and 7.5 ml (28.5 mmol) of triisopropyl phosphite (90%) are heated to 80° and stirred under a pressure of approximately 130 mbar for 18 hours. The excess triisopropyl phosphite is distilled off under reduced pressure and the evaporation residue is purified by chromatography on silica gel with ethyl acetate/methanol (9:1). 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21]([NH:20][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])=[O:22])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1ccnc(N)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccnc(NC(=O)Nc2cccc(Cl)c2Cl)c1
Yield: 91.3 %

Procedure:
A solution of 2-amino-4-tert-butylpyridine (192 mg) and 2,3-dichlorophenyl isocyanate (240 mg) in anh. toluene (15 mL) was heated at 70° C. under argon for 24 h. The resulting mixture was diluted with EtOAc (200 mL) then washed with water (125 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to give a gum. Trituration of the gum with hexanes afforded N-(4-tert-butylpyridyl)-N′-(2,3-dichlorophenyl) urea as a white solid (394 mg, 91%): TLC (2:1 hexanes/ethyl acetate) Rf 0.40; FAB-MS m/z 338 ((M+H)+). B2a. Reaction of a Heterocyclic Amine with N,N′-Carbonyldiimidazole Followed By Reaction with a Substituted Aniline
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:30][CH2:31][CH3:32])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:23]([N:17]([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:33])=[O:5])[C:9]([CH2:30][CH2:31][CH3:32])=[N:10][C:11]=2[CH:16]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C(C)C)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C(C)C)ccc2n1CC(=O)O

Procedure:
[5-(Benzyl-isobutyryl-amino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.55 (m, 1H), 7.25 (m, 6H), 7.03 (m, 1H), 5.14 (s, 2H), 4.88 (s, 2H), 3.20 (m, 2H), 2.80 (m, 1H), 1.72 (m, 2H), 1.25 (m, 6H), 0.95 (t, 3H). MS calculated for C23H27N3O3+H: 394, observed: 394.