Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][O:26]C1C=CN=C(CN)C=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[C:23]([O:26][CH3:25])[CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccnc(CN)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: COc1ccnc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)c1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(4-methoxypyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.07 (d, J=11.01 Hz, 3H), 1.23 (d, J=11.01 Hz, 2H), 1.47 (d, J=9.94 Hz, 2H), 1.60 (s, 3H), 1.88 (s, 3H), 2.25 (s, 3H), 4.73 (d, J=5.37 Hz, 2H), 7.22-7.29 (m, 2H), 7.59 (d, J=7.79 Hz, 1H), 8.53-8.56 (m, 2H), 12.88 (bs, 1H); MS (ESI) m/z 342.7 (M+1)+.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:27]=[CH:26][S:25][CH:24]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccsc3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccsc1

Procedure:
The 2-trifluoroacetamido-3-(thiophen-3-yl)-6-benzoyl-imidazo[1,2-a]pyridine (8.88 g, 21.4 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 5.51 g. (80.7%). EA, MS(FD).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16](C)=[CH:17][CH:18]=2)[C:13]([CH3:22])([CH3:21])[C:12]1=[CH2:23].ClC1C=C2C(=CC=1)N(C)C(=C)C2(C)C.COC1C=C2C(=CC=1)N(C)C(=C)C2(C)C.C(OC1C=C2C(=CC=1)N(C)C(=C)C2(C)C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:21])([CH3:22])[C:12]1=[CH2:23]
Reactant: C=C1N(C)c2ccc(C)cc2C1(C)C
Agent: C=C1N(C)c2ccc(Cl)cc2C1(C)C
Agent: C=C1N(C)c2ccc(OC)cc2C1(C)C
Agent: C=C1N(C)c2ccc(OCC)cc2C1(C)C
Solvent: COc1ccc(N)cc1
Product: C=C1N(C)c2ccccc2C1(C)C

Procedure:
If colour bases which are obtained by coupling 4-anisidine to 1,3,3,5-tetramethyl-2-methylene-indoline, 5-chloro-1,3,3-trimethyl-2-methylene-indoline, 5-methoxy-1,3,3-trimethyl-2-methylene-indoline or 5-ethoxy-1,3,3-trimethyl-2-methylene-indoline are used instead of the colour base obtained from 4-anisidine and 1,3,3-trimethyl-2-methylene-indoline and the procedure is otherwise the same, valuable cationic hydrazone dyestuffs are likewise obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[N+:12]([O-:15])([OH:14])=O.[N+:16]([O-])([OH:18])=[O:17]>N([O-])=O.[Na+]>[OH:1][C:2]1[C:11]([N+:12]([O-:15])=[O:14])=[CH:10][C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: O=[N+]([O-])O
Reactant: OCCOc1ccccc1O
Agent: O=N[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(OCCO)c(O)c([N+](=O)[O-])c1

Procedure:
An attempt to nitrate 2-(2-hydroxyphenoxy)ethanol with 3N nitric acid and sodium nitrite catalyst at 25°-30° C. was unsuccessful.
Reaction SMILES: [CH2:1]([C:3](=[CH:18][CH2:19][CH:20]1[CH2:24][CH:23]=[C:22]([CH3:25])[C:21]1([CH3:27])[CH3:26])[CH2:4][O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16])[CH3:2].C(OC(=O)C=CC1C=C(C)C=CC=1O)C>>[CH2:1]([C:3](=[CH:18][CH2:19][CH:20]1[CH2:24][CH:23]=[C:22]([CH3:25])[C:21]1([CH3:26])[CH3:27])[CH2:4][O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16])[CH3:2]
Reactant: CCC(=CCC1CC=C(C)C1(C)C)COC(=O)C=Cc1cc(C)ccc1O
Agent: CCOC(=O)C=Cc1cc(C)ccc1O
Product: CCC(=CCC1CC=C(C)C1(C)C)COC(=O)/C=C/c1cc(C)ccc1O

Procedure:
According to the same procedure, 3-(2-hydroxy-5-methyl-phenyl)-acrylic acid 2-ethyl-4-(2,2,3-trimethyl-cyclopent-3-enyl)-but-2-enyl ester was prepared from 3-(2-hydroxy-5-methyl-phenyl)-acrylic acid ethyl ester, 2-ethyl-4(2,2,3-trimethyl cyclopentyl-3-en-1-yl)-but-2-en-1-ol and tetraisopropyl-o-titanate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10]1([S:16]([C:19]2[C:20]([S:30][CH3:31])=[N:21][N:22]3[C:27](Cl)=[CH:26][C:25]([CH3:29])=[N:24][C:23]=23)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([S:16]([C:19]2[C:20]([S:30][CH3:31])=[N:21][N:22]3[C:27]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)=[CH:26][C:25]([CH3:29])=[N:24][C:23]=23)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCN1CCNCC1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Product: CSc1nn2c(N3CCN(CCO)CC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
0.26 g (2 mmol) of 1(2-hydroxyethyl)-piperazine was added to a solution of 0.35 g (1 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5 a]pyrimidine and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and he combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2,CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.36 g (73%) of 2-[4(3-benzenesulphonyl-5-methyl-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl) -piperazin-yl]-ethanol as colorless crystals, m.p. 189-190°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH:14]([CH2:15][CH2:16][C:17]=2[CH:18]=1)[CH:13]1[C:9]([CH3:33])([C:10](=[O:32])[C:11](=[CH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH2:12]1)[CH2:8][CH2:7]3.[BH4-].[Na+].C(OCC)(=O)C.O>C1COCC1.CO>[CH3:33][C:9]12[CH2:8][CH2:7][CH:6]3[CH:14]([CH2:15][CH2:16][C:17]4[CH:18]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=43)[CH:13]1[CH2:12][C:11](=[CH:19][C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1)[CH:10]2[OH:32]
Reactant: COc1cc(C=C2CC3C4CCc5cc(O)ccc5C4CCC3(C)C2=O)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C=C2CC3C4CCc5cc(O)ccc5C4CCC3(C)C2O)cc(OC)c1OC
Reaction time: 2 h

Procedure:
A solution of 3-Hydroxy-13-methyl-16-(3,4,5-trimethoxy-benzylidene)-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-one (448 mg, 1.0 mmol, CAB01124) in THF/methanol (1:1, 40 ml) was cooled to 0° C. (ice bath) and sodium borohydride (100 mg, 2.64 mmol) was added. The reaction mixture was stirred for 2 h at this temperature, while it was turning from slightly yellow to colourless. The solution was transferred into a separation funnel and ethyl acetate (100 ml) and water (100 ml) were added. The organic layer was separated, washed with water (50 ml) and brine (50 ml), dried over sodium sulphate and concentrated under reduced pressure. Yield 445 mg (99%) white solid. 1H-NMR (CDCl3, 400 MHz), δ: 0.74 (s, 3H), 1.20-1.60 (m, 6H), 1.90-1.98 (m, 1H), 2.01-2.08 (m, 1H), 2.21-2.41 (m, 3H), 2.74-2.90 (m, 3H), 3.86 (s, 3H), 3.89 (s, 6H), 4.15 (d, J=9.4 Hz, 1H, H-17), 4.62 (s, 1H, —OH), 6.49-6.51 (m, 1H), 6.59 (d, J=2.3 Hz, 1H), 6.63-6.68 (m, 3H), 7.18 (d, J=8.2 Hz, 1H). LRMS (FAB+): 451.3 (100, [M+H]+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23](Cl)(=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27].CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CCCCC(=O)Cl
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and pentanoyl chloride (0.36 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O for 18 h. The product was dried in vacuo to give pentanoic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.77 g, 35% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.71 min (95.58%); mp: 184-186° C.; 1H NMR (DMSO-d6) δ 0.81-0.95 (m, 3H, CH3), 1.28 (dq, J=7.3, 14.8 Hz, 2H, CH2), 1.41-1.64 (m, 2H, CH2), 1.97-2.13 (m, 1H, CHH), 2.17 (t, J=7.5 Hz, 2H, CH2), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-2.99 (m, 1H, CHH), 4.43 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.67-7.81 (m, 2H, Ar), 7.88 (d, J=7.7 Hz, 1H, Ar), 8.50 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.68, 21.79, 21.99, 27.37, 30.93, 34.98, 41.87, 48.99, 121.78, 123.48, 129.71, 131.59, 133.28, 147.84, 166.97, 167.12, 169.82, 172.47, 172.73; LCMS: MH=372; Anal Calcd for C19H21N3O5: C, 61.45; H, 5.70; N, 11.31. Found: C, 61.12; H, 5.54; N, 11.15.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClC(Cl)C>[CH:25]1([NH:31][C:32]([NH:1][C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:5]3=[N:6][CH:7]=2)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(N)nc12
Reactant: O=C=NC1CCCCC1
Solvent: CC(Cl)Cl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Yield: 75.8 %

Procedure:
A solution of 1-[2-amino-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.100 g, 0.287 mmol) and cyclohexyl isocyanate (0.37 mL, 2.9 mmol) in 3 mL of dichloroethane was stirred at reflux for 19 h, then concentrated to a residue. Column chromatography (10→50% EtOAc/hexanes) afforded 0.103 g (76%) of 1-cyclohexyl-3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a brown solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:24][C:25]([C:27]1[CH:28]=[C:29](Cl)[CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][N:33]([CH:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])[C:32]2=[O:44])=[O:26])[C@H:9]([OH:23])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCOCC1>[CH2:1]([C@H:8]([NH:24][C:25]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][N:33]([CH:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])[C:32]2=[O:44])=[O:26])[C@H:9]([OH:23])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(CCC)n1cnc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cc(Cl)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCC(CCC)n1cnc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cccc2c1=O
Yield: 100.2 %

Procedure:
195 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]-amino}propyl]-6-chloro-4-oxo-3-(1-propylbutyl)-3,4-dihydroquinazoline-8-carboxamide, 5 cm3 of dioxane and 30 mg of 10% (50% wet with water) palladium on carbon are stirred under 10 bar of hydrogen in an autoclave. Since the reaction does not develop, 30 mg of 10% dry palladium on carbon are added and the reaction mixture is stirred under 15 bar of hydrogen in an autoclave. The catalyst is filtered and the filtrate is concentrated under reduced pressure (5 kPa). 185 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-4-oxo-3-(1-propylbutyl)-3,4-dihydroquinazoline-8-carboxamide are obtained.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH2:29][C@@H:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:25]=[CH:26][C:27]=1[F:28])=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:29][C@@H:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CCOC(=O)[C@H](C)Cc1ccc(F)c(NC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@H](C)Cc1ccc(F)c(NC(=O)[C@@H](N)C(C)C(F)(F)F)c1
Reaction time: 8 h

Procedure:
2.36 g (4.61 mmol) of ethyl (2R)-3-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorophenyl]-2-methylpropanoate (Example 37A, mixture of 4 isomers) were dissolved in a mixture of 9.8 ml of ethanol and 9.8 ml of THF. The solution was inertized with argon, and 293 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen overnight. Following filtration through kieselguhr and washing with dichloromethane/methanol, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1) and separated. This gave 1.35 g of the target compound as diastereomer mixture 1 (77.2% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.CCCCCC>[CH2:18]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Reactant: CCCCNCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1

Procedure:
A solution of 1.46 g of phenyl N-(3-chlorophenyl)carbamate in 15 ml of tetrahydrofuran was added to a solution of 1.92 g of N-benzyl-n-butylamine in 20 ml of tetrahydrofuran and the mixture stirred under reflux for 24 hours. The mixture was diluted with hexane and the precipitate collected by filtration. Recrystallization from pentane afforded 1-benzyl-1-(n-butyl)-3-(3-chlorophenyl)urea, m.p. 69°-70° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1N

Procedure:
The title compound was prepared from (4-cyano-5-morpholin-4-yl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B3) (5.01 g, 14.4 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a pink solid (4.18 g, 91%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[N:28]1([C:32]([C:34]2[CH:39]=[CH:38][C:37](Br)=[CH:36][N:35]=2)=[O:33])[CH2:31][CH2:30][CH2:29]1>CC(N(C)C)=O>[N:28]1([C:32]([C:34]2[N:35]=[CH:36][C:37]([O:7][C:8]3[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=3)[C:11]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:12])=[CH:38][CH:39]=2)=[O:33])[CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(OC(C)C)c2)cn1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC(C)C)c2)cn1
Temperature: 160 °C
Yield: 32.2 %

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (144 mg, 0.5 mmol) and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (181 mg, 0.75 mmol) and bromotris(triphenylphosphine)copper (93 mg, 0.1 mmol) in DMA (5 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 4 hours. The mixture was cooled to RT and ambient pressure, partitioned between water (75 mL) and ethyl acetate (50 mL), the organic layer washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (crystallised from ether) (72 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 2.3 (m, 2H), 2.5 (s, 3H), 4.2 (t, 2H), 4.5 (m, 1H), 4.65 (t, 2H), 6.7 (s, 1H), 7.05 (s, 1H), 7.2 (s, 1H), 7.3 (d, 1H), 8.0 (br, 2H), 8.3 (br, 2H) and 9.45 (s, 1H). m/z 448 (M+H)+. Mpt (melting onset) 125.7° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](OC(=O)CC)(=O)[CH2:16]C.CN1C=CN=C1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH2:15][CH3:16])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCC(=O)OC(=O)CC
Agent: Cn1ccnc1
Product: CCC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
Treat a solution of 2-(4-fluoro-3-nitrophenyl)acetic acid (1.5 g, 7.53 mmol) in propionic anhydride (5.40 mL, 45.2 mmol) with 1-methylimidazole (0.600 mL, 7.53 mmol) and stir at RT overnight. Quench the mixture with H2O, stir for 1 h, extract with EtOAc (2×), wash the combined organics with satd. Na2CO3, then brine, dry the organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (830 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 8.00 (dd, J=7.4, 2.2 Hz, 1H), 7.61 (ddd, J=8.6, 4.6, 2.2 Hz, 1H), 7.53 (dd, J=11.4, 8.6 Hz, 1H), 3.95 (s, 2H), 2.56 (q, J=7.3 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 212.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH:5]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)[CH:18]=[C:17](Br)[CH:16]=1)[CH3:7])[CH3:2].[F:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1>>[CH2:1]([O:3][C:4](=[O:46])[CH:5]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:51]2[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=2)[CH:18]=[C:19]([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)[CH:20]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(Br)cc(-c2ccc3c(c2)OCCO3)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CCOC(=O)CCc1ccccc1OC(C(=O)OCC)C(C)CCCCCCOc1cc(-c2ccc(F)cc2)cc(-c2ccc3c(c2)OCCO3)c1
Yield: 33.8 %

Procedure:
A similar procedure as described in Example 22, step 2 was used, starting from 4-[3-{6-[3-bromo-5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-phenoxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (189 mg, 0.27 mmol) and 4-fluoro-phenylboronic acid (114 mg, 0.82 mmol) to obtain 4-[3-{6-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4′-fluoro-biphenyl-3-yloxy]-hexyl}-(2-(2-ethoxycarbonyl-ethyl)-phenoxy)-butyric acid ethyl ester (65 mg, 34%) as a light yellow oil: ES(+)-HRMS m/e calculated for C43H49FO8 (M+Na)+ 735.3303, found 735.3298.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]([CH3:14])=[CH:6][CH:7]=[CH:8][C:9]([CH3:13])=[CH:10][CH2:11][OH:12])[CH3:2]>CCOCC>[CH2:16]([O:15][CH:4]([O:3][CH2:1][CH3:2])[C:5]([CH3:14])=[CH:6][CH:7]=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=[O:12])[CH3:17]
Reactant: CCOC(OCC)C(C)=CC=CC(C)=CCO
Solvent: CCOCC
Product: CCOC(OCC)C(C)=CC=CC(C)=CC=O

Procedure:
31.1 g. of 1,1-diethoxy-2,6-dimethyl-2,4,6-octatrien-8-ol are dissolved in a mixture of 800 ml. of petroleum ether (boiling range 40°-45° C.) and 200 ml. of ether, and after the addition of 150 g. of manganous oxide, shaken for 16 hours at room temperature. The mixture is then filtered, washed with ether, and after evaporation of the filtrate, 22 g. of 1,1-diethoxy-2,6-dimethyl-2,4,6-octatrien-8-al is obtained, which can be used for the Wittig reaction without further purification. The aldehyde can be purified through adsorption on aluminum oxide (activity II deactivated with 2 per cent water and 0.5 per cent pyridine). A small portion is removed by washing with a petroleum ether/ether mixture (95:5). By elution with a petroleum ether/ether mixture (3:1), there is obtained pure 1,1-diethoxy-2,6-dimethyl-2,4,6-octatrien-8-al (Abs. Max. 325 mμ; E11 = 1200; nD24 = 1.5607). Melting point of the di-semicarbazone 242°-243° C. with decomposition.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=2)[N:3]=1.[Br:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1>>[Br:23][C:24]1[N:25]=[CH:26][N:27]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:28]=1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: Brc1c[nH]cn1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example A.38) (0.68 g, 2.0 mmol) and commercially available 4-bromo-imidazole (0.44 g, 3.0 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.79 g, 88%). MS (ISP) 452.9 [(M+H)+]; mp 191° C.