Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][S:30]([NH2:33])(=[O:32])=[O:31])[C:14]3=[O:34])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:37](Cl)(=[O:39])[CH3:38].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][S:30]([NH:33][C:37](=[O:39])[CH3:38])(=[O:32])=[O:31])[C:14]3=[O:34])=[CH:11][CH:12]=2)=[CH:35][CH:36]=1
Reactant: NS(=O)(=O)CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)CCN1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-2-[3-[4-(4-chloro-phenoxy)-phenyl]-2-oxo-4-(3-trifluoromethyl-phenyl)-imidazolidin-1-yl]ethanesulfonic acid amide (20 mg, 0.037 mmol) and acetyl chloride (6 mg, 0.076 mmol) in anhydrous CH2Cl2 (1 mL) is added triethylamine (7.7 mg, 0.076 mmol). The mixture is stirred at room temperature for 14 h and is then concentrated to dryness. The residue is dissolved in EtOH and treated with NaOH (0.074 mmol, 1 M aqueous solution) for 1 h. The mixture is then treated with water (3 mL) and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and purified by flash column chromatography to provide the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.56 (m, 3H), 7.48 (m, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 6.86 (d, J=9.2 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.26 (dd, J=9.2, 6.8 Hz, 1H), 4.00 (t, J=9.2 Hz, 1H), 3.75-3.90 (m, 2H), 3.55-3.65 (m, 2H), 3.36 (dd, J=8.8, 6.8 Hz, 1H), 2.17 (s, 3H); HPLC-MS calculated for C26H23ClF3N3O5S (M+H+) 582.1, found 582.1.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=1.[Cl-].[NH4+]>CCCCCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:6][CH:5]([CH2:7][O:8][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=1)[CH2:4][OH:3]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: OCC(O)CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnc(OCC(O)CO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3.3 g of sodium hydride (60% in oil, 82.5 mmol) which had been washed with hexane was dispersed in 150 ml of toluene under a nitrogen atmosphere, and to this suspension was dropwise added 7.5 g of glycerol while stirring with a mechanical stirrer to precipitate sodium alcholate. After completion of the addition, the stirring was continued for 30 minutes, followed by decantation to remove toluene and an addition of 150 ml of glycerol to the residue. After stirring for 15 minutes, 15 g of 2-chloro-3,5-dinitropyridine (73.7 mmol) was added by portions under ice-cooling. The mixture was stirred for 1 hour under ice-cooling and for a further 1 hour at room temperature, followed by an addition of 35 ml of saturated aqueous solution of ammonium chloride and extraction with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified over silica gel column chromatography (Silica gel 60 manufactured by Merk Co.; eluent: ethyl acetate:hexane=1:1-2:1) to obtain 19 g (73.2 mmol) of the title compound in the form of a yellow solid (yield: 99%). The compound can be further purified by a mixed solvent of ethanol-ether-hexane.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH:11]=[C:10]([CH:16]=[O:17])[C:9]2=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:19][OH:20]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH:11]=[C:10]([C:16]([O:20][CH3:19])=[O:17])[C:9]2=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCOc1ccc2occ(C=O)c(=O)c2c1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOc1ccc2occ(C(=O)OC)c(=O)c2c1
Reaction time: 0.5 h

Procedure:
6-Butoxy-4-oxo-4H-chromen-3-carbaldehyde (VI-2; 5 g, 0.02 mol) prepared by the method described in Steps 1 and 2 of the Reference Example 2 and N-bromo succinicimide (4.4 g) were refluxed in carbon tetrachloride (350 ml) for 1 h while it was irradiated externally with 250W Matsushita Electric tungsuten lamp. The mixture was allowed to cool in an ice-bath and anhydrous methanol (6 ml) was added slowly and stirred for additional 30 min. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed successively with water, 1 M sodium hydroxide, water and brine and dried. The solvent was evaporated under reduced pressure to give 6.2 g of an orange solid. Recrystallization from 95% ethanol afforded 4.3 g (77%) of compound (VII-3) as pale yellow prisms. m.p. 88-89° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:14][S:15]([NH:18][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:17])=[O:16]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
3-(tert-butoxycarbonylamino)propanoic acid (4 g, 21.2 mmol, 1.0 equiv) was dissolved in DCM (100 mL). Then methanesulfonamide (1.43 g, 15.1 mmol, 0.7 equiv), EDCI (3.45 g, 18.2 mmol, 0.85 equiv) and DMAP (0.37 g, 3 mmol, 0.15 equiv) were added to the mixture and stirred for 2 h at r.t. The reaction mixture was cooled down to 0° C., ice water (100 mL) was added. The mixture was stirred for 15 min, separated and the water layer was extracted twice with DCM. The combined organic layer was washed by 5% HCl, brine, dried over Na2SO4, concentrated to give tert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate as a gray oil (3.6 g, 90%). ESI-MS (M+H)+: 267.1. 1H NMR (400 MHz, DMSO-d6) δ: 6.91˜6.83 (brs, 1H), 3.36 (s, 3H), 3.19˜3.12 (m, 2H), 2.41 (t, 2H), 1.37 (s, 9H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@@H:13]([CH2:12][NH:30][CH2:27][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCNC[C@@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.7 g, 1.8 mmol), propan-1-amine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and flash column chromatography (EtOAc/MeOH). Yield: 0.4 g, 73%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 228° C. MS m/z (rel. intensity, 70 eV) 285 (M+, 3), 207 (4), 73 (5), 72 (bp), 70 (5). [α]=+67° (MeOH).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](Cl)=[O:4].[CH3:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[NH2:26]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:26][C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:9][CH3:8])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:4]
Reactant: O=C(Cl)C(F)(F)F
Reactant: CSCCCCCNc1c(N)cnc2ccccc12
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CSCCCCCNc1c(NC(=O)C(F)(F)F)cnc2ccccc12
Yield: 153.8 %

Procedure:
A cool solution of trifluoroacetyl chloride (3.5 g, 26.5 mmol) in toluene was slowly added to a solution of N4-[5-(methylthio)pentyl]quinoline-3,4-diamine (6 g, 23.1 mmol) in a mixture of toluene and pyridine. A heavy yellow precipitate formed. The reaction mixture was stirred over the weekend and then concentrated under reduced pressure to provide 13.2 g of crude 2,2,2-trifluoro-N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)acetamide.
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].CO.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:1][C@@H:2]([O:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CC[C@@H](C)Oc1ccc(OCC(=O)OC)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC[C@@H](C)Oc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the above ester (2.50 g), methanol (20 ml) and 5 ml of 10% NaOH is stirred at RT for 24 hours. The reaction is then worked up by addition of water and 10% sulfuric acid to adjust the pH to 3 and extraction with ether. The combined organic layers are washed with water and with brine, dried, filtered and the filtrate stripped to give (R)-(-)-4-(1-methylpropoxy)phenoxyacetic acid, [α]D20 -21.369°.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@@H:6]([C:9]([OH:11])=O)[CH2:7][OH:8])=[O:4].S(Cl)(Cl)=O>CO>[OH:8][CH2:7][C@H:6]1[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:9]1=[O:11]
Reactant: NCC(=O)N[C@H](CO)C(=O)O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: O=C1CNC(=O)[C@@H](CO)N1

Procedure:
A mixture of glycyl-D-serine I (4 g) in methanol (12 ml) was treated with thionyl chloride (4 ml) dropwise over a 15 min period maintaining the temperature below 30°. The mixture was heated at 40°-50° for 3 h, and the solvent was evaporated in vacuo. The residue was triturated under diethyl ether and then dissolved in methanol (80 ml). Aqueous ammonia (8 ml) was added and the resulting solid was filtered off, to give the title compound as a solid (1.95 g) m.p. 218°.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([CH:15]=O)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:1]1([CH2:7][O:8][C:9]2[C:10](/[CH:15]=[CH:21]/[C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ncccc1OCc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)/C=C/c1ncccc1OCc1ccccc1
Yield: 712.6 %

Procedure:
Crude 3-(phenylmethoxy)-2-pyridinecarboxaldehyde (30 g) and carbomethoxymethylenetriphenylphosphorane (55 g) in acetonitrile (800 ml) were stirred at reflux overnight. The solution was evaporated onto silica (Merck 9385) which was then purified by FCC eluting with ethyl acetate to give the product contaminated with triphenylphosphine oxide. This crude product was triturated with ether and the triturate was evaporated to an oil which was chromatographed on a column of silica (Merck 9385) eluting with cyclohexane followed by cyclohexane/ethyl acetate (4:1) to give the title compound as a yellow oil (270 g), t.l.c. (cyclohexane/ethyl acetate/triethylamine 80:20:1) Rf 0.17.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with the 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=402.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:43]=[CH:42][C:25]([CH2:26][N:27]2[C:32](=[O:33])[C:31]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=3)=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1.CC(C)([O-])C.[K+].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:27]2[C:32](=[O:33])[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[N:8]([CH2:7][C:6]6[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)[N:9]=[C:10]([CH3:18])[C:11]=45)=[C:36]([F:41])[CH:35]=3)=[CH:30][N:29]=[CH:28]2)=[CH:42][CH:43]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: O=c1c(-c2ccc(O)c(F)c2)cncn1Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cncn(Cc6ccc(Cl)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 137.1 %

Procedure:
To a 10 mL round bottom flask was added 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (13.0 mg, 0.0454 mmol), prepared according to the procedure of Example 43, Step E, 3-(4-chlorobenzyl)-5-(3-fluoro-4-hydroxyphenyl)pyrimidin-4(3H)-one (10 mg, 0.0302 mmol) prepared according to the procedure of Example 43, Step D and dissolved in DMF (0.5 mL). A 1M solution of potassium t-butoxide in THF (0.0454 mL, 0.0454 mmol) and potassium carbonate (6.27 mg, 0.0454 mmol) were both added and the resulting mixture was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and the crude mixture was partitioned between water (10 mL) and ethyl acetate (15 mL). The organic layer washed with brine, dried over sodium sulfate and evaporated to afford 24.1 mg of brown oil. The crude product was purified by silica gel chromatography (Biotage 12M), loading with chloroform and eluting with 1.5% MeOH in CHCl3 to afford the desired product as an off-white solid (5 mg, 28%). LRMS (APCI pos) m/e 583.2 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[CH2:11][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)CBr
Reactant: c1ccc2[nH]ccc2c1
Product: COC(=O)Cn1ccc2ccccc21

Procedure:
This compound was prepared from indole and methyl bromoacetate by the method described in Example 10, part i. The reaction mixture was worked up by concentrating in vacuo, diluting with water and extracting with ethyl acetate (3x). The combined extracts were washed with water (3x) and brine, dried and evaporated to an oil. The residue was purified by chromatography on flash silica eluting with petroleum spirit 40°-60° C.--diethyl ether (5:1, 2:1) to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15]>CCO.[Pd]>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][C:4]1[CH:5]=[C:6]([NH2:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1CCN(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1CCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [2-(2-methoxy-5-nitrophenyl)-ethyl]-dimethyl-amine (1.0 g, Step D) dissolved in EtOH (20 mL) was added 10% Pd/C (0.1 g). The reaction vessel was capped with a rubber septum and H2 gas was introduced through a balloon/needle. The reaction was stirred vigorously overnight at RT, and which time it was filtered through sand/Celite®. Concentration of the crude mixture provided a beige oil which was purified by chromatography on silica gel (97:3 CH2Cl2:MeOH) to afford pure 3-(2-dimethylamino-ethyl)-4-methoxy-phenylamine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.C([Li])(CC)C.CN(C)[CH:22]=[O:23].O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:6]([CH:22]=[O:23])[CH:7]=1
Reactant: CN(C)C=O
Reactant: CC1(C)COC(c2ccc(Cl)cc2)=N1
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(Cl)cc2C=O)=N1
Reaction time: 2 h

Procedure:
To a solution of 16 g (76 mM) of 2-(4-chlorophenyl- 4,4-dimethyl-4,5-dihydrooxazole in 60 ml of dry tetrahydrofuran at -78° C. under an inert atmosphere was added dropwise 75 ml of 1.4M sec-butyllithium in hexane. After 1 hour 9.7 ml of freshly distilled dimethylformamide in 20 ml of tetrahydrofuran was added and stirring was continued for 2 hours at room temperature. The mixture was poured into water (200 ml) and extracted with diethylether (2×100 ml), dried and evaporated to yield the crude product. Vacuum distillation, bp 140°-150° C./0.4 mm gave the title compound as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[F:13][CH:14]([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>CN(C)C=O>[F:26][CH:14]([F:13])[O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(OC(F)F)cc1)n1ccc2cc(I)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
5-Iodo-1H-indole (2.0 g, 8.23 mmol) was dissolved in dimethylformamide (DMF) (10 ml) and cooled to 0° C. Sodium hydride (494 mg, 12.34 mmol) was added in small portions. The reaction mixture was stirred for 1 hour at 0° C. 4-(Difluoro-methoxy)-benzenesulfonyl chloride (2.196 g, 9.05 mmol) was dissolved in DMF (5 ml), and added slowly to the reaction mixture. Stirring was continued for 45 minutes. Cold water (150 ml) was added to the reaction mixture. The reaction mixture was extracted twice with ethyl acetate (100 ml). The organic layer was dried over magnesium sulphate, filtered, and the solvent evaporated under reduced pressure to give a crystalline solid (3.0 g, 81%). ESI-MS [m/z]: 449.95 [M+H]+. 1H-NMR (500 MHz, d6-DMSO): δ=8.05 (d, 2H), 8.0 (s, 1H), 7.85 (d, 1H), 7.8 (d, 1H), 7.65 (d, 1H), 7.4 (t, J=70 Hz, 1H), 7.35 (d, 2H), 6.8 ppm (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 38.3 %

Procedure:
To a solution (20 ml) of ethyl 1-(3-cyano-4-neopentyloxyphenyl)pyrazole4-carboxylate (2 g) in ethanol was added 2 N aqueous sodium hydroxide solution (3.7 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solution of ethyl alcohol and water to give 0.7 g of 1-(3-cyano-4-neopentyloxyphenyl) pyrazole-4-carboxylic acid, melting point 199-200° C.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[C:16](OC(=O)C)(=[O:18])[CH3:17].S(=O)(=O)(O)O>>[C:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Agent: O=S(=O)(O)O
Product: CC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (5 grams), 25 milliliters of acetic anhydride and 0.1 milliliter of sulfuric acid were mixed with stirring at 25° C. for 15 minutes. The reaction mixture was then heated to reflux and refluxed for one-half hour, poured into ice with stirring, stirred for ten minutes and filtered. Filtration yielded the desired 1-acetoxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product as a solid. It was taken up in ether, dried over magnesium sulfate, and the ether evaporated. The product then melted at 103°-04° C.
Reaction SMILES: [Na].[H-].COCCO[Al+]OCCOC.[F:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22](O)=[O:23])=[CH:17][CH:16]=1.[OH-].[Na+]>C1C=CC=CC=1>[F:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[CH2:22][OH:23])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1Oc1ccc(F)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: OCc1ccccc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
36.1 ml of 70% sodium-bis-(2-methoxyethoxy) aluminum hydride in benzene are added dropwise over a one hour span to a stirring mixture of 15 g of 2-(4-fluorophenoxy)benzoic acid in 150 ml of benzene under nitrogen at ambient temperature. After total addition, the reaction mixture is stirred for an additional 30 minutes and then permitted to stand for 4 days. Thereafter, the reaction mixture is cooled to 0° C. before adding 100 mls of 10% sodium hydroxide while stirring. Following this addition, the layers separate and the aqueous layer is extracted twice with 100 ml portions of benzene. The combined benzene solutions are successively washed twice with 100 ml portions of water, washed once with 60 ml of saturated sodium chloride solution and dried, providing a clear yellow oil. The oil is distilled at 118.5°-121.5° C. and 0.07 mm pressure to provide the clear, colorless liquid, 2-(4-fluorophenoxy)benzyl alcohol.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.CC1C=CC(S([C:27]#[N:28])(=O)=O)=CC=1>C1COCC1>[Cl:11][C:9]1[N:8]=[CH:7][NH:6][C:5]2=[N:4][CH:3]=[C:2]([C:27]#[N:28])[C:10]=12
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cnc2[nH]cnc(Cl)c1-2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of anhydrous THF (40 ml) containing 5-Bromo-4-chloro-7H-pyrrolo[2,3-c]pyrimidine D3 (1 g) was added nBu-Li (2.5M, 5.2 ml, 12.9 mmol) dropwise at −78° C. under nitrogen. After this addition the resulting solution was stirred for 1 hour at −78° C. before adding 4-methylbenzenesulfonyl cyanide (935 mg, 5.2 mmol) and the resulting solution stirred for 1 hour at −78° C. and then allowed to warm up to room temperature overnight. The reaction was quenched with a saturated NH4Cl solution at 0° C., extracted with EtOAc (100 ml) and organic layer was washed with 5% NaHCO3 solution, dried Na2SO4, filtered and concentrated in vacuo to afford a yellow solid. Purified by flash chromatography on silica gel eluting with Pet Eth/EtOAc 1/2 to give the desired product D42 as a yellow solid in 350 mg. LCMS [MH+] 179.0 @1.17 min (5 min run)