Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:15]=[C:16]([F:32])[C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](=[O:31])[CH3:30])=[CH:23][CH:22]=2)=[N:18][CH:19]=1>[Na].C(O)C>[OH:5][C:3]1[CH:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[C:16]([F:32])=[CH:15][C:14]([C:13]([F:34])([F:33])[F:12])=[CH:19][N:18]=3)=[CH:26][CH:25]=2)[CH2:28][C:29](=[O:31])[CH:30]=1
Reactant: CC(=O)C=Cc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(O)=CC(=O)CC1c1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 1.0 liter flask was dissolved 2.4 g (0.104 mol) of freshly cut sodium metal in 10 mL of absolute ethanol. To this solution was added a solution of 15.6 g (0.0975 mol) of diethyl malonate in 25 mL of absolute ethanol followed by a solution of 30.2 g (0.0928 mol) of 1-(4-(5-(trifluoromethyl)-3-fluoro-2-pyridyloxy)phenyl)but-1-en-3-one in 75 mL of absolute ethanol. The mixture was stirred at ambient temperature for 6 hours and a cream colored solid precipitated from the solution. The mixture was then diluted with 250 mL of water and the solid slowly dissolved therein. To this solution was slowly added 12 mL of concentrated HCl and the desired product crystallized out of the solution. The product was recovered by filtration, thoroughly washed with water and dried in vacuo. The product melted at 161°-163° C., with decomposition; Rf -0.32 (silica gel, 10:90 MeOH:CHCl3), 1H NMR (CDCl3): δ 1.0 (t, 3H, CH3CH2 --), 2.3-3.1 (m, 2H, ring protons), 3.4-3.75 (m, 2H, ring protons), 3.96 (q, 2H, CH3CH2 --), 5.39 (s, 1H, vinyl), 7.10-8.2 (m, 6H, aromatic), 9.0-11.7 (b, 1H, --OH).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH2:8]([C@H:10]1[CH2:19][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:24][CH3:25])[N:16]=2)[NH:11]1)[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[CH:5]([O:4][C:2]([N:11]1[C:12]2[C:17](=[N:16][C:15]([O:24][CH3:25])=[CH:14][CH:13]=2)[C@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH2:19][C@@H:10]1[CH2:8][CH3:9])=[O:3])([CH3:7])[CH3:6]
Reactant: CC[C@H]1C[C@@H](NC(C)=O)c2nc(OC)ccc2N1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H]1C[C@@H](NC(C)=O)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
Add isopropyl chloroformate (3.10 mL, 2.82 mmol, 1.0 M in toluene) dropwise to a solution of (+/−)-cis-N-(2-ethyl-6-methoxy-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide (702 mg, 3.102 mmol) and pyridine (0.677 mL, 8.46 mmol) in dichloromethane (15 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 10 min. Add 1 M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure, to afford the title compound (895 mg, 95%). MS (ES+): 336 (M+H).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH2:9]O)[N:6]=[CH:5]1)[CH2:2][CH3:3].O=S(Cl)[Cl:13]>C(Cl)Cl>[Cl:13][CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCCn1cnc(CO)c1
Solvent: ClCCl
Product: CCCn1cnc(CCl)c1

Procedure:
(1-propyl-1H-imidazol-4-yl)methanol (535 mg, 3.11 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 4-(chloromethyl)-1-propyl-1H-imidazole. Then following General Procedure A, the title compound (587 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (744 mg, 4.66 mmol), 4-(chloromethyl)-1-propyl-1H-imidazole, K2CO3 (2.1 g, 15.54 mmol) in DMF (10 ml).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[N:24]1([C:29]2[CH:30]=[C:31]([C:35]3[O:40]C(C)(C)[O:38][C:37](=O)[CH:36]=3)[CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][N:26]=[CH:25]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:37](=[O:38])[CH2:36][C:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:30]=1)=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 68.8 %

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (154 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (135 mg, 0.5 mmol) according to the general procedure K. Obtained as an orange oil (179 mg).
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.F[C:25]1[C:34]([CH3:35])=[C:33]2[C:28]([C:29](=[O:43])[C:30]([C:40]([OH:42])=[O:41])=[CH:31][N:32]2[C@@H:36]2[CH2:38][C@@H:37]2[F:39])=[CH:27][CH:26]=1>CS(C)=O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:25]3[C:34]([CH3:35])=[C:33]4[C:28]([C:29](=[O:43])[C:30]([C:40]([OH:42])=[O:41])=[CH:31][N:32]4[C@@H:36]4[CH2:38][C@@H:37]4[F:39])=[CH:27][CH:26]=3)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(N2CC[C@@H](C3(N)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 427.3 %

Procedure:
After adding 3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidine (185 mg, 817 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (2 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (190 mg, 68 μmol) was added thereto and it was heated under reflux for 17 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (50 ml). After washing the organic layer with a 10% aqueous citric acid solution (25 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (5 ml) to the residue while cooling with ice, stirring at room temperature was performed for 30 minutes. 1 mol/l Hydrochloric acid (5 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (20 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution and the insolubles were removed by filtration. After adjusting the pH of the basic aqueous solution to 7.4 using 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×4) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by preparative chromatography (development at the lower layer of a 7:3:1 mixture of chloroform:methanol:water), recrystallized in ethanol, and dried under a reduced pressure. 112 mg (43%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: CS(C)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[OH-].[K+]>C(OC(=O)C)C>[N:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: c1c[nH]cn1
Reactant: COc1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccccc1-n1ccnc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a degassed DMSO (20 mL) solution of imidazole (1.0 g, 15 mmol) was added 2-bromoanisole (1.25 mL, 10 mmol), KOH (1.12 g, 20 mmol) and Cu2O (280 mg, 2 mmol) under nitrogen. The resulting mixture was stirred at 140° C. for 24 hrs under N2. After cooling to room temperature, the mixture was poured into ethylacetate (EA) (50 mL) and filtered. The filtrate was washed with water (50 mL×3) and dried over anhydrous magnesium sulfate. After rotary evaporation, the crude oil was purified via column chromatography on silica gel with eluent of EA/MeOH (9/1, v/v), affording a light yellow liquid (50%). 1H-NMR (400 MHz, CDCl3) δ(ppm) 7.79 (s, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 7.05 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)C(C)n1cc(Br)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(=O)O)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)propanoate (5.0 g, 18 mmol) in 40 mL of 1:1 THF/MeOH are rt was added 25 mL of 1N NaOH. The reaction was stirred at rt for 5 hours and was then acidified with 2N HCl to pH˜2. The solid formed was collected and was washed with water and EtOAc to give white solid (4.2 g, 94% yield) as desired product. MS (ESI pos. ion) m/z (MH+): 245.9. Calc'd Exact Mass for C8H8BrNO3: 244.97.
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:17][CH3:18])[C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([CH2:17][CH3:18])=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: CCC(OC(=O)c1ccccc1)C(=O)C(C)(C)C
Solvent: CN(C)C=O
Product: CCc1oc(-c2ccccc2)nc1C(C)(C)C
Temperature: 160 °C

Procedure:
0.31 g of 1-ethyl-3,3-dimethyl-2-oxobutyl benzoate is dissolved in 8 ml of dimethylformamide in a reactor. 0.75 g of thiourea (5 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 6 hours. The reaction mixture is extracted with dichloromethane and then washed 3 times with water, dried over anhydrous sodium sulphate, filtered and finally brought to dryness under vacuum.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[BH3-]C#N.[Na+].Cl>O.CO>[CH2:1]([NH:4][CH2:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCNCC1CCCCC1

Procedure:
To 100 mL of MeOH is added 2-propenylamine (5.7 g, 0.1 mol), 11.2 g (0.1 mol) of cyclohexane carboxaldehyde and 12 g (0.2 mol) of NaBH3CN. The pH is adjusted to 6 with concentrated HCl. Monitor the reaction by thin layer chromatography. Upon completion add concentrated HCl until gas evolution ceases. Add 300 mL of H2O and extract once with 200 mL of Et2O. Add 1N NaOH to the aqueous solution until it is basic (pH=11) and extract 2 times with 200 mL of Et2O. Dry the organic phase over Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:22])[O:20][CH3:21]>C(Cl)Cl.[NH4+].[Cl-]>[CH3:21][O:20][C:19]([N:9]([C:4]1[CH:3]=[C:2]([I:1])[C:7]([CH3:8])=[CH:6][N:5]=1)[C:19]([O:20][CH3:21])=[O:22])=[O:22]
Reactant: COC(=O)Cl
Reactant: Cc1cnc(N)cc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C(=O)OC)c1cc(I)c(C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 4-iodo-5-methylpyridin-2-amine (90 g, 380 mmol) in DCM (3800 mL) were added DIEA (192 mL, 930 mmol) and methyl carbonochloridate (58.8 mL, 760 mmol) at 0° C. The reaction mixture was allowed to stir at 0° C. for 1 h and was then diluted with aqueous saturated NH4Cl. The organic solvent was separated and the aqueous solution was extracted with DCM. The organic solutions were combined, washed with brine and concentrated to give dimethyl(4-iodo-5-methylpyridin-2-yl)imidodicarbonate (110 g, 80%) which was used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([N+:11]([O-])=O)[C:3]=1[NH2:4].Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:11])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(F)c(Br)c1N
Temperature: 25 °C

Procedure:
3-Bromo-4,5-difluoro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2-bromo-3,4-difluoro-6-nitroaniline (700 mg, 2.78 mmol) and SnCl2 ·2H2O (3.14 g, 13.9 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 75° C. for 2 h. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming ) to bring the pH to 5. The thick yellow white emulsion was then extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown oil which crystallized on standing to yield 410 mg (66%). 1H NMR (CDCl3) δ3.59 (br s, 4H, 2(NH2)); 6.52 (m, 1H, H-6).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[Si:14]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCn1ccc2cc(Br)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2cc(Br)ccc21

Procedure:
A solution of 1(2-hydroxyethyl)-5-bromoindole (6 gm, 0.025 mol), t-butyldimethylsilyl chloride (4.5 gm, 0.03 mol) and triethylamine (4.2 ml, 0.03 mol) in CH2Cl2 (60 ml) was stirred for 12 hours at room temperature. The reaction mixture was then washed twice with H2O, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound as a yellow oil. 1H NMR was consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]([C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:22][CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of (4-chlorophenyl)boronic acid (1.50 g, 9.59 mmol), 4-nitrobenzoyl chloride (1.78 g 9.59 mmol), bis(triphenylphosphine)palladium(II) chloride (0.137 g, 0.192 mmol) and K3PO4 (3.34 g, 19.2 mmol) in toluene (30 mL) was treated as described in WO 2010/015355 to provide the title compound.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].CN(C=O)C.[F:19][C:20]1[N:21]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[C:23]([CH:25]=O)[N:24]=1>C(COC)OC>[C:1]([CH:3]=[CH:25][C:23]1[N:24]=[C:20]([F:19])[N:21]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:2]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: N#CC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Examples 15 and 16: Diethyl cyanomethylphosphonate was converted to its anion with sodium hydride in dimethoxyethane solution. An equal volume of DMF was added, followed by 2-fluoro-4-formyl-1-triphenylmethylimidazole. Reaction at room temperature gave 4-(2-cyanovinyl)-2-fluoro-1-triphenylmethyl imidazole. A suspension of this in MeOH was reduced by magnesium turnings to give 4-(2-cyanoethyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 2.71 (t, 4H); 6.42 (s, 1H); 7.1-7.4 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([C:19]#[C:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:9][N:8]=1.[H][H]>O1CCCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([CH2:19][CH2:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:9][N:8]=1
Reactant: COc1ccc(CNc2nnc(C#CC3(O)CCCC3)c3ccc(C#N)cc23)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(CCC3(O)CCCC3)c3ccc(C#N)cc23)cc1Cl
Yield: 57.4 %

Procedure:
690 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopentyl)-1-ethynyl]-6-phthalazine carbonitrile was dissolved in 200 ml tetrahydrofuran, 50 mg of 10% Pd—C was added thereto, and the mixture was stirred for 0.5 hr in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was evaporated. The resulitng residue was purified by silica gel column chromatography to give 400 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopentyl)ethyl]-6-phthalazine carbonitrile. This product was converted in a usual manner into the hydrochloride.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:40]([OH:44])[CH:41]([CH3:43])[CH3:42]>>[CH2:40]([O:44][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)CO
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CC(C)COc1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 20 (65 mg, 0.12 mmol) was reacted with 2 equivalents each of n-butyl lithium and isobutyl alcohol by the procedure described in Reference Example 6 and 7 to yield the title compound: HPLC/MS: m/e=535 (M++1); Rt=5.28 min. 1H-NMR 400 MHz (CDCl3): 0.97 (d, J=7 Hz, 6H), 2.07 (m, 1H), 4.01 (d, J=7 Hz, 2H), 6.90-6.94 (m, 1H), 7.05-7.10 (m, 1H), 7.12-7.28 (m, 7H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2].[CH2:11]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:20][O:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:15]1)[CH2:12][CH3:13]>C1(C)C(C)=CC=CC=1>[C:28]1([CH3:31])[CH:27]=[CH:26][C:25]([S:22]([OH:24])(=[O:21])=[O:23])=[CH:30][CH:29]=1.[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:20][CH:16]1[O:17][CH2:18][CH2:19][N:14]([CH2:11][CH2:12][CH3:13])[CH2:15]1)[CH3:2]
Reactant: CCCN1CCOC(COS(=O)(=O)c2ccc(C)cc2)C1
Reactant: CCOc1ccccc1N
Solvent: Cc1ccccc1C
Product: CCCN1CCOC(CNc2ccccc2OCC)C1
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
A solution of 2-ethoxyaniline (4.8 g.) and 4-n-propyl-2-toluene-p-sulphonyloxymethylmorpholine (10 g.) in xylene (50 ml.) is heated under reflux in an atmosphere of nitrogen for 60 hours. A resinous solid separates from the solvent which is distilled under reduced pressure. The residual sticky solid is washed with ether to give a yellow solid which is crystallised from methanol/ether to give 2-(2-ethoxyanilino)methyl-4-propylmorpholine toluene-p-sulphonate, m.p. 169°-172°C.
Reaction SMILES: Cl.Cl.ClC1[C:8]([N:9]([CH2:16][CH3:17])[C:10](=[O:15])[CH2:11][CH2:12][NH:13][CH3:14])=[CH:7][N:6]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:5]=1.CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:35])[CH3:34].[CH2:37]([Cl:39])Cl>>[Cl:39][C:37]1[C:8]([N:9]([CH2:16][CH3:17])[C:10](=[O:15])[CH2:11][CH2:12][N:13]([CH3:14])[C:33](=[O:35])[CH3:34])=[CH:7][N:6]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:5]=1
Reactant: CCN(C(=O)CCNC)c1cn(-c2cccnc2)nc1Cl
Reactant: CC(=O)Cl
Reactant: ClCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)CCN(C)C(C)=O)c1cn(-c2cccnc2)nc1Cl
Reaction time: 16 h

Procedure:
To a stirred solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methylamino) propanamide dihydrochloride (0.060 g, 0.16 mmol) in CH2Cl2 (0.5 mL) was added DIPEA (0.081 g, 0.60 mmol) followed by acetyl chloride (0.019 mg, 0.24 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was then diluted with CH2Cl2 and washed with water. The organic phase was separated, dried, concentrated, and then purified by silica gel chromatography eluting with 0%-10% MeOH/CH2Cl2 to afford the title compound F64 as a colorless oil (0.025 g, 45%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[CH3:21][S:22]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(C(C#N)=NO)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)=NOS(C)(=O)=O)cc1C
Yield: 93 %

Procedure:
23.2 g (0.13 mol) of α-hydroxyimino-3,4-dimethylbenzylcyanide are reacted with 27.2 ml (0.20 mol) of triethylamine and 11.1 ml (0.14 mol) of methansulfonyl chloride in tetrahydrofuran, as described under 3.2. After the usual processing, 32.6 g of a crude product are obtained, which is then recrystallised from isopropanol, giving 30.5 g (93%) of α-(methyl-sulfonyloxyimino)-3,4-dimethylbenzylcyanide in the form of a brownish powder having an m.p. of 91-95° C.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[N:9][C:8]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)C>O.C1COCC1>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][C:8]2[N:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]=2[C:6]([OH:31])=[O:5])=[CH:24][CH:25]=1)#[N:30]
Reactant: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.2 g (8.4 mmol) of lithium hydroxide was added to a stirred solution of 2,6-bis(4-cyano phenoxy)-nicotinic acid ethyl ester, 1.6 g (4.15 mmol), in a mixture of 5 ml of water and 2.5 ml of THF (2:1) at 5° C. and the contents were stirred for 3 h at RT. The reaction mixture was washed with diethylether. 6 N HCl was added to aqueous layer with stirring until the solution attained a pH of 2. The white precipitate obtained was collected, washed with water and dried under reduced pressure to afford 1.1 g of the required product. Percentage purity (LCMS): 83.2%, (M+1)=357.0+1. 1H NMR (DMSO-d6): δ 6.98 (1H, d), 7.26 (4H, d), 7.80 (4H, d), 13.22 (1H, brs).