Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:33]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])#[N:34].C(O)(=O)C.N1CCCCC1>C(O)C>[C:33]([C:35](=[CH:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:13]2[N:14]=[C:15]3[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=2)=[CH:22][N:21]=1)[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])#[N:34]
Reactant: CN(C)C(=O)CC#N
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)nc3)nc12
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Yield: 75 %

Procedure:
In a 50 ml three necked round bottom flask, 5-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)picolinaldehyde (0.17 g, 0.00037 mole) and 2-cyano-N,N-dimethylacetamide (0.084 g, 0.00075 mole) was taken in ethanol (5 ml). Piperidine acetate (3.3 M solution in water) (0.2 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed for 4 hrs and after completion of the reaction, the ethanol was distilled out and water was added to residue. Aqueous layer was extracted with ethyl acetate, organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was triturated with n-pentane, the pentane layer was decanted and solid was dried under vacuum to yield 0.152 g of 2-cyano-N,N-dimethyl-3-(5-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl-amino)pyridin-2-yl)acrylamide which was converted to the title compound as described in Example 8 above.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[C:8]([N:11]([C@H:15]([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C(=O)[O-])(C)C>C1COCC1>[CH3:8][NH:11][C@H:15]([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H](Cc1ccccc1)N(C(=O)[O-])C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H](C)Cc1ccccc1
Temperature: 0 °C
Yield: 105.1 %

Procedure:
To a stirred suspension LiAlH4 (0.77 g, 20.4 mmol) in THF (120 mL) was added a solution of 1,1-dimethylethyl[(1R)-1-methyl-2-phenylethyl]carbamate (2.4 g, 10.2 mmol) in THF (30.0 ml) dropwise at 0° C., and then the reaction mixture was heated at reflux for 2 hours. The mixture was cooled to 0° C., and quenched by addition of ice (1.0 g), then 15% aqueous sodium hydroxide (1.0 mL) followed by water (0.5 mL). The lithium salts were collected by filtration and washed with Et2O (200 mL). The filtrate was dried (Na2SO4), filtered and concentrated. The resulting residue was distilled at reduced pressure to afford the title compound (1.6 g) as a light yellow oil. LC-MS (ES) m/z=150 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1N.Cl.N([O-])=O.[Na+].[F:15][B-](F)(F)F.[H+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[F:15]
Reactant: F[B-](F)(F)F
Reactant: Nc1cc(Br)ccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: Fc1cc(Br)ccc1Cl
Yield: 70.4 %

Procedure:
2-Chloro-5-bromoaniline (258 g) is added to concentrated hydrochloric acid (750 ml) and the mixture is stirred at 80°-90° C. until formation of a homogeneous suspension. Then, it is cooled and diazotized at 0°-5° C. by dropwise addition of sodium nitrite (95.1 g) in water (330 ml) during 1 hour. The mixture is stirred for an additional 20 minutes and then a solution of fluoroboric acid (700 ml) (prepared by dissolving 264 g of boric acid in 744 ml of 40% hydrofluoric acid) is added. After 30 minutes of stirring, the separated fluoroborate was filtered, washed successively with a small amount of a fluoroboric acid solution, ethanol and ether, and dried thoroughly in air and in vacuo. The thermal decomposition of the fluoroborate is carried out in two portions. Each portion is heated in a flask with a direct flame, the internal temperature during the decomposition being 130°-170° C. The distillates are combined and shaken with water (250 ml) and ether (250 ml). The ethereal layer is washed with 10% sodium hydroxide solution, 3 N-HCl and water and dried over sodium sulfate. The ether is evaporated and the residue is distilled, yielding 184.2 g (70%) of 2-chloro-5-bromofluorobenzene, b.p. 130°-142° C./20 Torr.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[CH2:15]([OH:20])[C:16]#[C:17][CH2:18][OH:19].C(N(CC)CC)C>ClCCCl.C[C]1[C](C)[C](C)[C](C)[C]1C.C1CC=CCCC=C1.Cl[Ru]>[CH3:12][O:11][C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:2]2[C:17]([CH2:18][OH:19])=[C:16]([CH2:15][OH:20])[O:14][N:13]=2)[CH2:4][CH2:5]1)=[O:10]
Reactant: COC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Reactant: OCC#CCO
Agent: Cl[Ru]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Solvent: C1=CCCC=CCC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](c2noc(CO)c2CO)CC1
Reaction time: 20 h

Procedure:
To a mixture of trans-methyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (0.900 g, 4.10 mmol) and but-2-yne-1,4-diol (0.370 g, 4.30 mmol) in 1,2-dichloroethane (41.0 ml) was added chloro(1,5-cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium(II) (0.0778 g, 205 μmol) and triethylamine (0.713 ml, 5.12 mmol) at room temperature. The reaction mixture was stirred for 20 h. The solvent was evaporated. The residue was triturated in ethyl acetate (50 ml). The solids were removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.758 g, 69%) as light brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH:34]1[CH2:37][CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[N:34]1([S:20]([C:16]2[CH:15]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH2:37][CH2:36][CH2:35]1
Reactant: C1CNC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC4)c3)n2)n1
Yield: 52.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.200 g, 0.409 mmol) by treatment with commercially available azetidine [CAS-no. 503-29-7] (0.14 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 53%) as a white solid. MS (ISP) 510.2 [(M+H)+]; mp 158° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][C:28]5[CH2:29][NH:30][CH2:31][C:24]=5[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)c(F)c2c1=O
Reaction time: 8 h
Yield: 74.4 %

Procedure:
0.6 g of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.2 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 1.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were suspended in 20 ml of acetonitrile, and then the reaction mixture was refluxed for 10 hours. This reaction mixture was kept overnight at the room temperature, and the produced precipitate was filtered and then the residue was washed with ethanol to obtain 0.58 g the title compound (yield 74%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Br[CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CCOC(=O)CCCBr
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: CCOC(=O)CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and ethyl 4-bromobutyrate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (80%) as a gummy material: 1H NMR (300 MHz, CDCl3) δ 7.29 (t, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 6.99 (d, 1H), 6.48 (s, 1H), 6.18 (s, 1H), 5.84 (d, 2H), 4.76 (ABq, 2H), 4.11 (q, 2H), 3.88-3.71 (m, 2H), 2.40 (t, 2H), 2.03 (t, 2H), 1.21(t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.4, 172.8, 156.0, 148.9, 142.4, 142.2, 132.4, 129.0, 124.0, 123.3, 119.4, 108.7, 103.0, 101.5, 93.6, 80.5, 60.7, 58.2, 39.6, 31.2, 22.6, 14.3; MS (ES+) m/z 418.08 (M+23), 396.1 (M+1).
Reaction SMILES: C(O)(=O)CCCCC(O)=O.C(O)CCCCCO.[N:19]([CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]([CH2:31][N:32]=C=O)([CH3:30])[CH2:23]1)=C=O>C(Cl)(Cl)(Cl)Cl>[NH2:19][CH:22]1[CH2:27][C:26]([CH3:28])([CH3:29])[CH2:25][C:24]([CH2:31][NH2:32])([CH3:30])[CH2:23]1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: O=C(O)CCCCC(=O)O
Agent: OCCCCCCO
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(N)CC(C)(CN)C1
Temperature: 100 °C

Procedure:
As in Example 8, a preadduct is prepared from 21 parts, by weight, of a polyester of adipic acid and 1,6-hexane diol (hydroxyl number 134.1; acid number 0.7) and 12.05 parts, by weight, of 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethyl cyclohexane by heating the mixture for 3 hours at 100° C. After dilution with 61.1 parts, by weight, of carbon tetrachloride, the solution is maintained at a temperature of 70° C. The mixture is reacted to form a polyurethane-polyurea in the same way as in Example 1, 1.628 kg/h of 1-amino-3-aminomethyl-3,5,5-trimethyl cyclohexane being additionally introduced as further reaction component into the reaction mixture by means of a pinned disc mixer following the preheater and the reactor being heated using saturated steam under 25 bars pressure. A 25% solution in isopropanol-toluene-methyl glycol acetate (50:37:13) prepared immediately after the production of the reaction product has a viscosity of 10,190 cP/20° C. After storage for 1 week at room temperature, the final viscosity amounts to 13220 cP/20° C.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:26]=1>C1(C)C=CC=CC=1>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[N:26]=[C:22]([CH:21]=[P:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: Fc1ccc(-c2csc(CBr)n2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2csc(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 60 °C
Yield: 13.2 %

Procedure:
Triphenylphosphine (4.82 g, 18.38 mmol) was added to a solution of 2-(bromomethyl)-4-(4-fluorophenyl)thiazole (5 g, 18.38 mmol) in toluene (30.0 mL) and the reaction was refluxed at 60° C. for 2 h. A precipitate was formed which was filtered and washed with ether (10 mL) thrice to provide 4-(4-fluorophenyl)-2-((triphenylphosphoranylidene)methyl)thiazole (1.1 g, 10.89%), which was carried through without further purification. MS (ESI) m/z: Calculated for C28H21FNPS: 453.11. found: 454.0 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH2:14][OH:15])[CH:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO>[OH:15][CH2:14][CH2:13][N:6]1[CH:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[NH:8][C:7]1=[O:12]
Reactant: [H][H]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)N1CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ccccc2C(c2ccccc2)N1CCO
Yield: 91 %

Procedure:
A mixture of 14 parts of 6-chloro-3,4-dihydro-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinone, 5 parts of sodium acetate and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is stirred in 2,2'-oxybispropane. The solid product is filtered off and stirred in 200 parts of water. It is filtered off again and dried, yielding 11.2 parts (91%) of 3,4-dihydro-3-(2-hydroxyethyl)-4-phenyl-2(1H)-quinazolinone; mp. 141° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]1>C(#N)C.O>[CH3:9][O:8][C:7]1[C:2]([O:1][CH2:29][C:30]2([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]2)=[C:3]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:4]=[CH:5][C:6]=1[O:10][CH3:11]
Reactant: COCC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1
Temperature: 70 °C

Procedure:
To a stirring solution of 4-(2-Hydroxy-3,4-dimethoxy-phenyl)-indan-1-one (Compound 303) (100 mg, 0.352 mmol) in acetonitrile (15 mL), were added potassium carbonate (145 mg, 1.056 mmol) and 3-(bromomethyl)-3-(methoxymethyl)oxetane (102 mg, 0.528 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afforded the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[CH:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>[Zn]>[OH:14][C:12]([CH3:13])([CH:11]=[CH:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC(=O)C=CCCc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccc(Cl)cc1

Procedure:
Using 7.17 g of 6-(p-chlorophenyl)-3-hexen-2-one, 4.2 ml of ethyl bromoacetate and 2.47 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 6.4 g of ethyl 3-hydroxy-3-methyl-7-(p-chlorophenyl)-4-heptenoate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.BrC1C=[CH:20][C:19]([C:22](C)(C)C)=[CH:18]C=1>>[C:19]([C:6]1[CH:5]=[CH:4][C:3]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[CH:2][CH:7]=1)([CH3:22])([CH3:20])[CH3:18]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C[C@@H]1CN(c2ccccc2F)CCN1
Product: C[C@@H]1CN(c2ccc(C(C)(C)C)cc2)CCN1
Yield: 27 %

Procedure:
The title compound was prepared following the procedure of Intermediate 5 but starting from 1-bromo-4-tert-butylbenzene. Purification by chromatography using dichloromethane/methanol (8/2) as eluent afforded The title compound as a liquid (1.5 g, 27%). M+(ESI): 233.3. HPLC (Condition A), Rt: 2.8 min (HPLC purity: 96.6%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]#[N:8])[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[N+:19]([O-])=O)=[N:3]1.N.O.S>C(O)C>[NH2:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:4]1[C:5]([C:7]#[N:8])=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: Cn1cc(C#N)c(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])n1
Agent: N
Agent: S
Solvent: O
Solvent: CCO
Product: Cn1cc(C#N)c(Nc2ccc([N+](=O)[O-])cc2N)n1

Procedure:
1-Methyl-3-(2,4-dinitroanilino)pyrazole-4-carbonitrile (2.88 g) was stirred in a mixture of 0.88 ammonia solution (60 ml), water (90 ml) and ethanol (60 ml) under reflux whilst a slow stream of hydrogen sulphide gas was bubbled through for 2 hours. The mixture was cooled, filtered and the residue crystallised from ethyl acetate-n-hexane to give the title compound m.p. 204° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(S)cc1
Reactant: Ic1ccccc1
Product: COc1ccc(Sc2ccccc2)cc1

Procedure:
The general procedure was used to convert iodobenzene and 4-methoxybenzenethiol to the title product. Purification by flash chromatography (hexane/CH2Cl2 [3:1] as the eluent) gave the analytically pure product as a clear oil (410 mg, 95% yield). 1H NMR (300 MHz, CDCl3) δ 7.27 (dt, J=8.85, 2H; Ha, Ha′), 7.12–6.96 (m, 5H; HC, Hc′, Hd, Hd′, He), 6.75 (dt, 2H; Hb, Hb′), 3.67 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 159.76 (C4), 138.56 (C8), 135.32 (C2, C6), 128.86 (C9, C13), 128.10 (C10, C12), 125.68 (C11), 124.19 (C1), 114.92 (C3, C5), 55.27 (C7). Anal. Calcd. for C13H12OS: C, 72.19; H, 5.59; S, 14.82; Found C, 72.26; H, 5.59; S, 14.65.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17]([O:19]CC)=O)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:36]O.Cl>CO.O.C(Cl)Cl>[C:30]([C:28]1[CH:27]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@H:13]([C:15]2[O:22][NH:36][C:17](=[O:19])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:33])([CH3:32])[CH3:31]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 105.4 %

Procedure:
Trans-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.734 g, 1.60 mmol) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.064 g, 1.60 mmol) dissolved in water (0.500 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.098 mL, 1.60 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 4 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8 mL, 48.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.723 g, 106%) as a yellow semi-solid. MS m/z 429 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:39]=[C:40]=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: CCCCCCCCN=C=O
Product: CCCCCCCCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 75 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.348 g of octyl isocyanate according to the general procedure of Example 21. Chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (90:10:1) then switching to ethyl acetate:ethanol:triethylamine (9:2:1) gave 1.011 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]-pyrimidin-7-yl}-3-octyl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=601; mp 54.5°-57.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC[C@H](C)Oc1cc(C)ccc1C=O
Yield: 35 %

Procedure:
A mixture (S)-(4-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (260 mg, 1.260 mmol), Dess-Martin periodinane (642 mg, 1.513 mmol) in DCM (10 mL) was stirred at rt for 1 h. It was then diluted with EtOAc, washed with sat. NaHCO3 and water. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (S)-4-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (90 mg, 35%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 6.87-6.78 (m, 2H), 5.88 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.21-5.10 (m, 2H), 4.59 (sxt, J=6.1 Hz, 1H), 2.63-2.51 (m, 1H), 2.51-2.42 (m, 1H), 2.40 (s, 3H), 1.40 (d, J=6.1 Hz, 3H).