Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:14][CH2:15][N:16]1C(=O)C2=CC=CC=C2C1=O.C1(=O)C2C(=CC=CC=2)C(=O)N1.O.NN>CN(C=O)C.CCO>[CH2:15]([NH2:16])[CH2:14][O:10][CH2:9][CH2:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOCCO
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Agent: [H-]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCOCCOCCN
Reaction time: 1.5 h
Yield: 37 %

Procedure:
A mixture of ethylene glycol mono-n-hexyl ether (15.0 g, 0.1 mol) and sodium hydride (0.1 mol) was dissolved in dry DMF (150 mL). After the mixture was stirred for 1-2 hours, N-(2-bromoethyl)phthalimide (25.4 g, 0.1 mol) was added with continued stirring and the mixture was warmed on a steam bath for 8 h. The DMF was then removed by evaporation and the residue dissolved in hot toluene, and the solution was concentrated to remove solvent. The residue was purified using silica gel chromatography using ethyl acetate to give 25 g (78%). 1H NMR (CDCl3, TMS): δ 0.87 (t, 3H, J=6.8Hz), 1.24˜1.30 (m, 8H), 1.56˜1.60 (m, 2H), 3.47 (t, 3H, J=6.8 Hz), 3.72 (dd, 2H, J1=4.4 Hz, J2=5.6 Hz), 4.06 (t, 3H, J=9.6 Hz), 4.41˜4.46 (m, 4H) 7.50˜7.52 (m, 2H), 7.72˜7.76 (m, 2H). A solution of the thus-derived isoindoledione and hydrazine hydrate (5.5 g, 0.11 mol) in EtOH (200 mL) was heated at reflux for 8 hours. The precipitate (phthalhydrazide) was removed by filtration, and the filtrate was concentrated to low volume and refiltered. The filtrate was then concentrated to dryness, treated with water (20 mL) and sodium hydroxide (11 g), and extracted with methylene chloride (4×100 mL). The combined organic layers are dried over MgSO4, concentrated, and purified by silica gel to provide 7 g of the amine product (50%). 1H-NMR (CDCl3, TMS): δ 0.89 (t, 3H, J=6.8 Hz), 1.29˜1.36 (m, 6H), 1.55˜1.60 (m, 2H), 2.03 (m, 2H), 3.45˜3.49 (m, 4H), 3.53˜3.55 (m, 2H), 3.71˜3.74 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=[O:4].[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:24]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=[O:4])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4'-(2-Bromoacetyl)methanesulfonanilide (Temple, D. L. et al., J. Med. Chem., 19(5), 626-633 (1976)) (40 g) and dibenzylamine (Aldrich Chemical Co., Milwaukee, Wis. 53233) (55.2 g) were combined in acetone (550 ml) and stirred 3 hours at ambient temperature. A heavy precipitate of dibenzylamine.HBr was filtered off. The filtrate was evaporated and crystallized first from MeOH and then from 2-PrOH. This yielded the product, 4'-(2-dibenzylaminoacetyl)methanesulfonanilide (XXVI) as a crystalline solid, 42.9 g, m.p. 131°-134°, whose thin layer chromatography analysis (silica, EtOAc/hexane) and NMR indicated a single compound with the structure indicated above.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1F
Temperature: 50 °C

Procedure:
19.3 g (0.085 mol) of 2,4-difluoro-3-trifluoromethylbenzoic acid are added in portions at room temperature to 130 ml of thionyl chloride. After metering has ended, the mixture is heated at 50° C. until the evolution of gas has ceased. The excess thionyl chloride is then removed by distillation and the crude product is reacted further directly.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)Cl>[CH2:4]([C@H:5]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[O:12][C:6]1=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: O=CCCc1ccccc1Cl
Reactant: COC(=O)/C=C/C(=O)c1ccco1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C=C(c2ccco2)OC(=O)[C@H]1Cc1ccccc1
Yield: 94 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-methyl 4-oxo-4-furanylbut-2-enoate using 0.5 mol % 1 as the catalyst in 94% yield as an 8:1 mixture of diastereomers (brown oil). [α]D20 (c 1.03, CHCl3)=+119.5; 1H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 4H), 7.18-7.16 (m, 2H), 6.67 (d, 1H, J=3.4 Hz), 6.47* (dd, 1H, J=3.2, 2.0 Hz), 6.45 (dd, 1H, J=3.2, 1.6 Hz), 5.74 (d, 1H, J=7.0 Hz), 5.70* (d, 1H, J=6.0 Hz), 3.77 (s, 3H), 3.68* (s, 3H), 3.55 (dd, 1H, J=14.3, 4.7 Hz), 3.52-3.46* (m, 1H), 3.40-3.35* (m. 1H), 3.29-3.26 (m, 1H), 3.15* (dd, 1H, J=13.6, 5.6 Hz), 3.03-2.97 (m, 1H), 2.90* (dd, 1H, J=13.6, 10.0 Hz), 2.74 (dd, 1H, J=14.3, 10.1 Hz); 13C NMR (100 MHz, CDCl3) δ 170.8, 168.4, 146.5, 145.3, 143.7, 138.0, 131.6, 129.6, 129.4, 128.9, 128.8, 127.4, 127.1, 111.8, 109.0, 108.9, 96.4, 94.0, 53.6, 52.9, 52.8, 43.0, 42.6, 40.8, 40.2, 35.5, 33.4; IR (thin film) ν 3063, 3029, 2953, 1781, 1734, 1495, 1455, 1264, 1225, 1201, 1174, 1085, 1009 cm−1; HRMS (ESI) calcd for C18H16O5 [M+Na]+ 335.0889, found 335.0890; 99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 20:1 hexanes/i-PrOH), tr (3S,4S)=31.9 min, tr (3R,4R)=22.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14](OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1>C=O.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[CH3:14])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Cl)c1
Agent: C=O
Solvent: O=CO
Product: CN1CC[C@H]1COc1cncc(Cl)c1

Procedure:
A 500 mg sample of 5-chloro-3-(N-t-butoxycarbonyl-2-(S)-azetidinylmethoxy)pyridine, prepared as in Example 39a above, was dissolved in 3 mL of 37% HCHO and 1.5 mL of HCOOH, and the reaction mixture was stirred at 100° C. for 40 minutes. The reaction was quenched by addition of H2O The mixture was adjusted to pH 7 with NaHCO3 and extracted with methylene chloride, the extract was dried over MgSO4, and the solvent was removed to give the title compound (181 mg). MS (DCI/NH3) m/e: 213/215 (M+H)+. 1H NMR (CDCl3, 300MHz) δ: 8.22 (d, J=2.5 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.23 (dd, J=2.5, 1.9 Hz, 1H), 4.01 (d, J=5.1 Hz, 2H), 3.52-3.44 (m, 1H), 3.45-3.35 (m, 1H), 2.94-2.83 (m, 1H), 2.41 (s, 3H), 2..15-2.04 (m, 2H).
Reaction SMILES: O.[C:2]([CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17])(=[O:4])[NH2:3]>[Fe].C(O)(=O)C>[C:2]([CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17])(=[O:4])[NH2:3]
Reactant: COc1ccc([N+](=O)[O-])cc1NCC(N)=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N)cc1NCC(N)=O
Temperature: 0 °C

Procedure:
Into 180 ml of water one adds 45 g of powdered iron and 15 ml of acetic acid. One brings this mixture under agitation to a temperature of 85° C. then one adds, little by little, 0.2 mol (45 g) of 2-carbamylmethylamino-4-nitro anisole. One maintains the reaction mixture for 10 minutes at 90° C. One adds soda to obtain a pH of 7.5, and then filters it hot. The filtrate is cooled to a temperature of 0° C. The expected product which precipitates is drained, washed with very little water, dried, recrystallized in methylisobutylketone. It melts at 144° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-])=O.[Cl-].[NH4+].[In]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-n1cncn1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Product: N#Cc1cc(N)ccc1-n1cncn1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
5-Nitro-2-[1,2,4]triazol-1-yl-benzonitrile (1.14 g, 5.3 mmol) was dissolved in ethanol (23 mL) and satd. aq. ammonium chloride (5.3 mL) before adding indium powder (3.25 g, 28.2 mmol). The mixture was then refluxed for 3 h, cooled to RT, and the solids filtered (MeOH washed). The filtrate was diluted with water, basified with 1N NaOH (aq), and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated under vacuum to yield the title compound (0.88 g). MS (ESI+) for m/z 186 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[N:17]=[C:16]([CH3:18])[C:15]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([O:22]C)=[O:21])=[C:14]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:13]=2)[CH2:7][CH2:6]1)[CH3:4]>CO>[CH2:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[N:17]=[C:16]([CH3:18])[C:15]([CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([OH:22])=[O:21])=[C:14]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[N:13]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(CC)CC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCN(CC)CC2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 55.7 %

Procedure:
A solution of sodium hydroxide 5N (0.5 mL) was added to a mixture of methyl 2-(2-(4-ethyl-1,4-diazepan-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.030 g; 0.070 mmol) in methanol (1.5 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 3 and 4 by addition of a solution of hydrochloric acid 6N. The aqueous layer was extracted with ethyl acetate and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (HPLC method 5) furnished 0.016 g (60%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)C.CC1N=C(NC)N=C(C(O)=O)C=1>>[CH3:27][C:25]1[CH:26]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[C:6]([CH3:29])[N:5]=[C:4]([NH:3][CH3:1])[N:9]=3)[O:14][N:13]=2)[CH:16]=[C:17]([CH3:28])[C:18]=1[O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Agent: CNc1nc(C)cc(C(=O)O)n1
Product: CNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{2,6-Dimethyl-4-[5-(6-methyl-2-methylamino-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 6-methyl-2-methylamino-pyrimidine-4-carboxylic acid; LC-MS: tR=0.75 min*; [M+H]+=386.15.
Reaction SMILES: [CH:1]1([CH:10]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:21]([N-:23][CH2:24][CH3:25])[CH3:22].[CH2:26]([N-:28][CH2:29][CH3:30])[CH3:27].[CH2:31]([N-:33][CH2:34][CH3:35])[CH3:32].C([N-]CC)C.[Zr+4:41]>>[CH2:21]([N-:23][CH2:24][CH3:25])[CH3:22].[CH2:26]([N-:28][CH2:29][CH3:30])[CH3:27].[CH2:31]([N-:33][CH2:34][CH3:35])[CH3:32].[Zr+3:41].[CH:12]1([CH:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH3:11])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: [Zr+4]
Agent: CC(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Agent: CC[N-]CC
Product: [Zr+3]

Procedure:
Bis(indenyl)ethane (0.327 g, 1.27 mmole) were reacted with zirconium tetra(diethyl amide) (1.025 g, 2.70 mmole, 6% excess for 1:2 stoichiometry) at 125° C. for 21/2 hours under nitrogen. This resulted in a light orange-yellow oil: 0.427 g of it were dissolved in 25 ml hexanes (46.1 mmole Zr/ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[CH3:24].[CH2:25]([N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:24])=[CH:18][C:19]([NH:23][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:34])=[CH:20][C:21]=1[CH3:22]
Reactant: COc1cc2nccc(Oc3c(C)cc(N)cc3C)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3,5-dimethyl-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=240-242° C.; LCMS m/z=585 (M+1); 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.84 (s, 1H), 8.41 (d, 1H, J=5 Hz), 7.61 (s, 1H), 7.55 (s, 1H), 7.45-7.33 (m, 6H), 6.19 (d, 1H, J=6 Hz), 4.01 (q, 2H, J=8 Hz), 3.95 (d, 6H, J=5 Hz), 2.07 (s, 6H), 1.30 (t, 3H, J=7 Hz).
Reaction SMILES: [O:1]1[CH2:4][C:3](=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2]1.[NH3:11]>C(O)C>[NH2:11][C:3]1([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][O:1][CH2:2]1
Reactant: N
Reactant: CCOC(=O)C=C1COC1
Solvent: CCO
Product: CCOC(=O)CC1(N)COC1
Temperature: 100 °C
Yield: 100 %

Procedure:
Ethyl oxetan-3-ylideneacetate (Preparation 38, 781 g, 5.49 mol) was dissolved in 2M ammonia in ethanol (8.24 L) and heated to 100° C. in a bomb for 5 hours. The reaction was concentrated in vacuo to afford the title compound as a mobile oil (750 g, 100% yield).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][O:28][CH2:29][C:30]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)=[O:31])[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>C(O)C>[OH:31][CH:30]([C:32]1[CH:33]=[CH:34][C:35]([C:36]#[N:37])=[CH:38][CH:39]=1)[CH2:29][O:28][CH2:27][C:25]1[N:24]=[CH:23][N:22]([C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:26]=1
Reactant: N#Cc1ccc(C(=O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium borohydride is added in portions to a solution of 1 mmol of 4-[2-(1-trityl-1H-imidazol-4-ylmethoxy)acetyl]benzonitrile in 12 ml of ethanol at 0° C. The reaction solution is stirred at room temperature for 12 hours, then poured into ice-water and stirred for 15 minutes. The mixture is adjusted to pH 5 by adding glacial acetic acid and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[CH:11]=[C:12]([CH3:14])[CH3:13])=[O:5].S(=O)(=O)(O)O>>[CH3:13][C:12]([CH3:14])=[CH:11][C@H:7]1[C:8]([CH3:9])([CH3:10])[C@@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Agent: O=S(=O)(O)O
Product: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Yield: 80 %

Procedure:
The water layer was made acidic with sulfuric acid and extracted with toluene (20 g) two times. The toluene layer was washed and distilled under reduced pressure to give trans-chrysanthemic acid (4.2 g; trans-isomer, 80.0 %). B.P. 122° to 130°C/3.3 mmHg.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(F)c1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(Nc2cccc(F)c2)S/C1=C\c1ccc2ncncc2c1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 3-fluoroaniline and DIEA to give 2-(3-fluoro-phenylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 351 (MH+).
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].S(=O)(=O)(O)O.S(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:19]1[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=[CH:17][C:18]=1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1ccc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 202.1 %

Procedure:
1,3-Dibromo-5,5-dimethylhydantoin (86.9 g, 0.298 mol) was added in about 5 g portions to a solution of p-nitrocumene (X) (100 g, 0.581 mol, GC purity 96%) and sulphuric acid (178 g, 1.743 mol, 98% strength) over a period of 5 hours. The mixture was then warmed to room temperature and stirred for another 1 hour. The reaction mixture was poured onto 200 g of ice water and admixed with sodium bisulphite (15.1 g, 0.06 mol) and toluene (300 g). The phases were then separated. The organic phase was washed with 5% strength aqueous sodium hydroxide and the toluene was distilled off under reduced pressure. 2-Bromo-1-isopropyl-4-nitrobenzene (147 g, 93.6 GC-% by area, 97% of theory) was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:12][N:13]([CH2:15][C:16](=[CH2:19])[C:17]#[N:18])C>>[C:17]([CH:16]([CH2:15][NH:13][CH2:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:19][NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])#[N:18]
Reactant: CCCCCCCCCCN
Reactant: C=C(C#N)CN(C)C
Product: CCCCCCCCCCNCC(C#N)CNCCCCCCCCCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To stirred n-decylamine (47.2 g., 0.3 mole) at 20° C. is added dropwise 2-[(N,N-dimethylamino)methyl]-2-propenenitrile (11.0 g., 0.1 mole) over a 3 minute period. The reaction mixture, protected from moisture with an Ascarite drying tube, is stirred at room temperature an additional three hours. It is then heated at 80° C. for 48 hours. The mixture is fractionally distilled under reduced pressure to remove a small amount of unreacted, excess n-decylamine, 2-cyano-N-(n-decyl)-N',N'-dimethyl-1,3-propanediamine as byproduct, and finally the product, 2-cyano-N,N'-di(n-decyl)-1,3-propanediamine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.[C:11]([NH:14][C:15](=[CH2:20])[C:16]([O:18][CH3:19])=[O:17])(=[O:13])[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]([NH:14][C:15](=[CH:20][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:13])[CH3:12]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: Cc1cc(Br)cc(C)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1cc(C)c(Cl)c(C)c1)NC(C)=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere 30.0 g (136.7 mmol) 5-bromo-2-chloro-1,3-dimethylbenzene, 24.0 g (164.0 mmol) methyl 2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrile were combined with 3.4 g (10.9 mmol) tri-o-tolyl-phosphane and 2.4 g (10.9 mmol) Pd(OAc)2 and stirred for 18 h at 80° C. The precipitate was suction filtered, the filtrate was evaporated down i. vac., combined with 800 mL DCM and 800 mL water, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was stirred with EtOAc, suction filtered and dried i. vac.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:7]2[C:12]([O:14]C)=[O:13].CO.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:7]2[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C1c2cccc(Br)c2CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1C(=O)O
Temperature: 0 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
To a solution of Intermediate 4B (5.0 g, 13.50 mmol) in THF (60 mL)/MeOH (60 mL) was added 1N NaOH (40.5 ml, 40.5 mmol). After 24 h, the reaction mixture was concentrated and the remaining aqueous layer cooled to 0° C. and the pH was adjusted to 5 using 1.0N HCl solution. The solution was extracted with EtOAc (3×75 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to give 4.75 g (99%) of Intermediate 4 as a white solid. 1H NMR (500 MHz, DMSO-d6) δ: 7.55 (dd, J=17.2, 7.8 Hz, 2H), 7.20 (t, J=7.8 Hz, 1H), 5.49-5.32 (m, 1H), 3.86-3.73 (m, 1H), 3.59-3.48 (m, 1H), 2.92-2.74 (m, 2H), 1.42 (d, J=12.9 Hz, 9H) ppm.
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:7][C:8]1[N:13]=[C:12]([S:14][CH3:15])[C:11]([F:16])=[CH:10][N:9]=1.C(N(CC)CC)C.II.Cl>C1COCC1.COCCOC.O>[C:1]([C:10]1[C:11]([F:16])=[C:12]([S:14][CH3:15])[N:13]=[C:8]([Cl:7])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CSc1nc(Cl)ncc1F
Agent: Cl
Agent: II
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)nc(C(C)(C)C)c1F
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of tert-butylmagnesium chloride (7.5 mL, 1M solution in THF, 7.5 mmol) in THF (15 mL) was added slowly a solution of 2-chloro-5-fluoro-4-(methylthio)pyrimidine (0.9 g, 5.0 mmol) in 1,2-dimethoxyethane (5 mL). The reaction mixture was stirred at 15° C. for 1 hour, then cooled to 0° C. and triethylamine (0.7 mL, 5.0 mmol) was added, followed by the addition of a solution of iodine (1.3 g, 5.0 mmol) in tetrahydrofuran (3 mL). Water (10 mL) was added to quench the reaction and pH was adjusted to 1 using 6N hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (2×15 mL). The combined organic phases were washed with aqueous sodium thiosulfate and then brine, dried over MgSO4, filtered and concentrated in vacuo to give a brown solid which was used without further purification.