Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:32][C:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[C:36]([CH3:47])[NH:35][N:34]=1>>[CH3:32][C:33]1[C:37]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:22]=[CH:21][CH:20]=[C:19]5[C:15]=4[C:16]([CH3:31])=[N:17][N:18]5[CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)=[C:36]([CH3:47])[NH:35][N:34]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(-c6c(C)n[nH]c6C)ccn45)cccc32)n1

Procedure:
Prepared according to procedure of Example 68, using 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (CDCl3, δ) 9.55 (d, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.78 (d, 1H), 7.62 (s, 1H), 7.42 (t, 1H), 7.34 (t, 1H), 7.15 (d, 1H), 7.06 (t, 2H), 6.52 (d, 1H), 5.64 (s, 2H), 2.87 (s, 3H), 2.58 (s, 3 h), 2.40 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].CCOCC.[CH3:16][N:17]([CH3:25])[CH2:18][CH2:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>O>[CH:22]1([C:20]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:21])[CH2:19][CH2:18][N:17]([CH3:25])[CH3:16])[CH2:24][CH2:23]1
Reactant: CN(C)CCC(=O)C1CC1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(O)(CCN(C)C)C2CC2)cc1
Temperature: 25 °C

Procedure:
The Grignard reagent prepared from 86 g. (0.46 mole) of 4-bromoanisole and 11.2 g. (0.46 mole) of magnesium metal in 200 ml. of dry ether was cooled to -20°C. and treated dropwise with 30 g. (0.23 mole) of cyclopropyl 2-dimethylaminoethyl ketone in 100 ml. of dry ether. After addition the mixture was allowed to warm to room temperature, then hydrolyzed with water and worked up as described in Preparation I. The oily product was distilled at 110°-115°C./0.1 mm.; the yield of free base was 16 g. (28%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[C:21]#[N:22].Cl.[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[C:21]#[N:22]
Reactant: COc1ccc(-c2ccc3c(C#N)c(OC)ccc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1c(O)ccc2cc(-c3ccc(O)cc3)ccc12

Procedure:
The title compound was prepared by reacting 2-methoxy-6-(4-methoxyphenyl)-1-napthonitrile (0.115 g, 0.397 mmol) with pyridinium HCl (4 g) at 190° C. according to method D to yield 0.025 g (24%) of a tan solid: mp>220° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.37 Hz), 7.28 (1H, d, J=9.07 Hz), 7.63 (2H, d, J=8.42 Hz), 7.88-7.98 (2H, m), 8.12-8.16 (2H, m), 9.63 (1H, s), 11.65 (1H, bs); MS (ESI) m/z260 (M−H)−
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:25])[CH:8]([OH:24])[CH2:9][NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]2.C(N(CC)CC)C>ClCCl>[CH3:5][O:6][C:7]([C@@H:8]1[O:24][C:1](=[O:2])[N:10]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([F:21])[CH:20]=2)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]3)[CH2:9]1)=[O:25]
Reactant: COC(=O)C(O)CNc1cc(F)c2c(c1)CCC(=O)N2C
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)CCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Phosgene (20% solution in toluene, 4.07 ml, 7.69 mmol) is added dropwise at 0° C. to 3-(8-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-2-hydroxypropionic acid methyl ester (Step 4, 1.81 g, 6.41 mmol) and triethylamine (2.23 ml, 16.0 mmol) in dichloromethane (25 ml). The mixture is allowed to warm to room temperature and stirred for an additional hour. The reaction is washed with 2N aqueous hydrochloric acid and saline, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography (50% ethyl acetate/hexane) to give the title compound as a white solid (1.71 g, 83%); MS (m/z): [M+H]+=323.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[CH2:24]([O:26][C:27](=O)[C:28]#[C:29][CH2:30][O:31]C)C>C(Cl)(Cl)Cl>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:30](=[O:31])[CH:29]=[C:28]([CH2:27][O:26][CH3:24])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: CCOC(=O)C#CCOC
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Solvent: ClC(Cl)Cl
Product: COCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 20) and 4-methoxy-but-2-ynoic acid ethyl ester (see Example 106) employing the procedure described in Example 95. [α]D25 −14.55 (c 0.495, CHCl3).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu](C#N)[C:14]#[N:15]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1[C:14]#[N:15]
Reactant: N#C[Cu]C#N
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1N
Reaction time: 0.08 h

Procedure:
In a 20 mL microwave vial, 2-bromo-4-(trifluoromethyl)aniline (238 mg, 1 mmol) and copper cyanide (90 mg, 1 mmol) were dissolved in N-methylpyrrolidone (NMP) (10 mL). The reaction was placed in a microwave reactor for 5 minutes at 200° C. The crude was dissolved in ethyl acetate and the precipitate was removed by filtration. The clear solution was washed with water. The organic layer was collected, dried over sodium sulfate, and evaporated under vacuum. The residue was purified by Varia HPLC (10% acetonitrile/water) to give the title compound.
Reaction SMILES: [OH-].[Li+].C[C@H]1[C@H](C2C=CC=CC=2)OC(=O)N1[C:16](=[O:27])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH3:18].C(OCC)(=[O:30])C>O1CCCC1.O>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C@H:17]([CH3:18])[C:16]([OH:27])=[O:30]
Reactant: CCOC(C)=O
Reactant: COc1ccccc1[C@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@@H]1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1[C@H](C)C(=O)O
Reaction time: 3 h

Procedure:
1.52 g of lithium hydroxide are added to a solution, cooled to +5° C., of 4.1 g of (4S,5S)-4-methyl-5-phenyl-3-[2-(2-methoxyphenyl)-(S)-propionyl]-oxazolidin-2-one in 60 cm3 of tetrahydrofuran and 30 cm3 of water. The reaction mixture is stirred at this temperature for 3 hours and, after returning to room temperature, ethyl acetate is added, the mixture is decanted, the aqueous phase is acidified with an aqueous 1N solution of hydrochloric acid and extracted with ethyl acetate, and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallised from hexane, filtered off and dried. 0.4 g of (S)-2-(2-methoxyphenyl)-propionic acid is obtained in the form of white crystals which melt at 102° C. [α]D20 =+84.6° (c=1; CHCl3).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])(=O)C.[CH2:18](O)[CH2:19][CH3:20]>OS(O)(=O)=O.C(OCC)C>[CH2:18]([O:14][C:12](=[O:13])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([O:15][CH2:16][CH3:17])[CH:7]=1)[CH2:19][CH3:20]
Reactant: CCOc1cc(CC(=O)O)ccc1OC(C)=O
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCOC(=O)Cc1ccc(O)c(OCC)c1
Temperature: 90 °C

Procedure:
Intermediate 4 (1.40 g, 5.87 mmol) was dissolved in an excess of 1-propanol (50 mL), concentrated H2SO4 (3 drops) was added, and the mixture was heated at 90° C. for ˜18 hours. The volume of 1-propanol was reduced under vacuum, then the mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate solution (2×), distilled water (1×), brine (1×), dried over magnesium sulfate and solvent was removed under vacuum, giving intermediate 5 as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](C(O)=O)[CH:5]=[CH:4][C:3]1=2.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: Cc1cccc2c1CCCC2=O
Temperature: 60 °C
Yield: 87 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (22.0 g, 116 mmol) in methanol (132 mL) was added sulfuric acid (22.7 g, 231 mmol) and the solution was heated to 60° C. for 4 h. Crystallization started when the solution was cooled, and then water (130 mL) was added. The slurry was filtered and the solid dried under vacuum to afford methyl 5-oxo-5,6,7,8-tetrahydronapthalene (20.6 g, 101 mmol, 87%) as an off-white solid. MS ESI calcd for C12H12O3 [M+H]+ 205, found 205.
Reaction SMILES: N([O-])=O.[Na+].C(O)(=O)C.N[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17]2)=[CH:12][CH:11]=1.[BrH:23]>S(=O)(=O)(O)O>[Br:23][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][CH:14]=2)[CH:19]=1
Reactant: Nc1ccc2ccc([N+](=O)[O-])cc2c1
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ccc(Br)cc2c1
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of NaNO2 (1.1 g, 24 mmol) in sulfuric acid (8.4 ml) was added at 0° C. acetic acid (8.9 ml) and 7-amino-2-nitro-naphthalene (2.1 g, 1mmol). This solution was added to a suspension of CuBr (2.5 g, 39 mmol) in conc. HBr (16 ml) at 0° C. and the mixture was stirred for 1 hour. The mixture was poured on ice and the aqueous phase was extracted with methylene chloride. The crude product was purified by chromatography to give 1.9 g (7.4 mmol, 51%) of the title compound, MS: m/e=251.2 (M+).
Reaction SMILES: C[O:2][C:3](=[O:50])[CH2:4][N:5](CC(OC)=O)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:44])=[O:43])=[CH:38][CH:37]=2)[CH:7]=1.[OH-].[Na+]>CO>[CH3:44][S:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][CH2:32][O:31][C:8]2[CH:7]=[C:6]([NH:5][CH2:4][C:3]([OH:50])=[O:2])[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=2)=[CH:41][CH:40]=1)=[O:43]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)=O)cc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(NCC(=O)O)cc(OCCCOc2ccc(S(C)=O)cc2)c1

Procedure:
A solution of 0.73 g (1.02 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine methyl ester and 0.68 ml (4.08 mmol) of 6N NaOH in 30 ml of methanol was stirred at reflux under argon for 4 hours. The methanol was removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from acetone-hexane to give 0.57 g (82% yield, mp 124°-126°) of N-(carboxymethyl)-N-[3-[3-[4-(methylsulfinyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl glycine.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:12][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3cc(NC(=N)c4cccs4)ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CC=C(c2c[nH]c3cc(NC(=N)c4cccs4)ccc23)CC1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A solution of compound 124 (0.14 g, 0.310 mmol) in CH2Cl2 (5 mL) was treated with 40% TFA in CH2Cl2 (5 mL) at 0° C. and the resulting solution was stirred at same temperature for 3 h. The solvent was evaporated, crude was diluted with 10% cold NH4OH solution (25 mL) and precipitated solid was filtered off. Crude product was dried and purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 125 (0.095 g, 88%) as a solid. 1H NMR (DMSO-d6) δ 1.36-1.48 (m, 1H), 1.90-1.98 (m, 2H), 2.34 (s, 3H), 2.38-2.64 (m, 4H), 6.07 (brs, 1H), 6.30 (brs, 2H), 6.58 (dd, 1H, J=1.2, 8.4 Hz), 6.81 (s, 1H), 7.09 (t, 1H, J=4.2 Hz), 7.20 (d, 1H, J=2.1 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.68-7.72 (m, 2H), 10.79 (s, 1H); ESI-MS (m/z, %) 351 (MH+, 100), 119(91); ESI-HRMS calculated for C20H23N4S (MH+); calculated: 351.1637; observed: 351.1638.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:57])[CH:48]([O:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH3:49])[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:57])[CH:48]([O:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH3:49])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CC(Oc1ccccc1)C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(Oc1ccccc1)C(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-2-phenoxypropanamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparative HPLC. (0.062 g, 59% yield over 2 steps): 1H NMR (CD3OD) δ 8.73 (s, 1H), 8.17 (t, 1H), 8.1 (d, 1H), 7.8–7.67 (m, 3H), 7.51 (t, 1H), 7.34–7.27 (m, 2H), 7.06–6.95 (m, 3H), 4.87 (q, 1H), 1.68 (d, 3H); ES-MS (m/z) 425 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.CN(C)C=O.[H-].[Na+]>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(-n2ccnc2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a mixed solution of methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (3.0 g), imidazole (0.82 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.5 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into iced water, and the precipitated crystals were collected by filtration to give methyl 3-[4-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-5-oxazolyl]propionate (1.6 g, yield 80%) as crystals. Recrystallization from methanol gave colorless prism crystals. melting point: 95–96° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]([O:47][CH2:48][C@H:49](O)[CH3:50])([CH3:46])[CH3:45].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:23][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:49]([CH3:50])[CH2:48][O:47][C:44]([CH3:46])([CH3:45])[CH3:43])[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(O)cc(Oc2cnc(C(=O)N(C)C)cn2)c1
Reactant: C[C@@H](O)COC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(C)(C)C)c1
Temperature: 0 °C

Procedure:
To methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-hydroxy-benzoate (10 g, 32 mmol) was added triphenylphosphine (10.3 g, 39.4 mmol), THF (100 mL) and (2R)-1-[(2-methylpropan-2-yl)oxy]propan-2-ol (CAS no. 136656-73-0) (5.21 g, 39.4 mmol). The resulting slurry was cooled to 0° C. and diethylazodicarboxylate (50% w/v in toluene, 13.7 mL, 39.4 mmol) was charged dropwise keeping the temperature below 10° C. After 2 hours the solvent was evaporated under reduced pressure and taken up with ethyl acetate (23 mL). A solid crashed out which was filtered and the mother liquors were evaporated under reduced pressure, taken up into ethyl acetate (23 mL) and isohexane (53 mL) and the resulting solid filtered, the mother liquors were evaporated under reduced pressure and the resulting residue was purified by flash chromatography eluting with 80% ethyl acetate/20% isohexane to afford the product (13.5 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:8]([CH2:9]O)=[CH:7][N:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:4]=1.S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:9][C:8]1[C:3]([C:2]([F:22])([F:21])[F:1])=[N:4][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ncc(CCl)c(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.4 %

Procedure:
A cooled (0° C.) solution of 0.081 g (0.25 mmol) of [4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol in 2.5 ml dichloromethane was treated with 0.04 ml (0.50 mmol) thionylchloride and stirred for 14 h at RT. The reaction was evaporated, dissolved in ether and twice in heptane and evaporated to give 0.077 g of pure 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:13][N:14]=[C:15]=[S:16]>ClCCl>[CH3:13][NH:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:16]
Reactant: CN=C=S
Reactant: Nc1ccccc1N1CCCC1
Solvent: ClCCl
Product: CNC(=S)Nc1ccccc1N1CCCC1

Procedure:
Reaction of 1-(2-aminophenyl)pyrrolidine (10 g) with methyl isothiocyanate (6.3 g) in dichloromethane (45 ml) at room temperature for 4 days gave 1-methyl-3-[2-(1-pyrrolidinyl)phenyl]thiourea (m.p. 125°-126° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12](O)=[O:13].CCCCCCC>CCOC(C)=O>[F:9][C:10]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The title compound can also be prepared according to the following method: 4-methylphenol (80.0 g, 739.8 mmol) was added to a suspension of 2,4,5-trifluorobenzoic acid (136.8 g, 776.8 mmol) and 1,1-carbonyldiimidazole (83-85% wt, 163.6 g, 849.7 mmol) in EtOAc (1.20 L) at 40° C. The reaction mixture was stirred at 40° C. for 2 hours, then cooled to 20° C. and washed with water (480 mL), a 0.5 M aqueous solution of sodium hydroxide (2×400 mL) and water (400 mL). The organics were concentrated in vacuo and azeotroped with heptane to give a yellow oil. Heptane (640 mL) was added and the mixture was stirred at room temperature for 16 hours. A seed was used to facilitate the formation of a precipitate. The resulting suspension was cooled to 10° C. and filtered. The residue was washed with cold heptane (80 mL) and dried to afford the title compound as an off white solid (147.5 g, 75%):
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH2:11])[O:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][C:21]#[N:22]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][C:21]([NH:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:4][CH2:3][CH2:2][O:1]2)=[NH:22]
Reactant: NC1CCCCC12OCCO2
Reactant: N#CNc1c(Cl)cccc1Cl
Product: N=C(Nc1c(Cl)cccc1Cl)NC1CCCCC12OCCO2
Reaction time: 0.75 h
Yield: 43.5 %

Procedure:
1,4-Dioxaspiro[4.5]dec-6-ylamine (500 mg) was reacted with 2,6-dichloro-phenylcyanamide (595 mg, prepared as described in J. Med. Chem., 1975, 18, 90-99) at 130° C. After 45 minutes, the reaction was stopped and the reaction product was purified by preparative HPLC. The product-containing fractions were combined, the acetonitrile was stripped off in a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with dichloromethane. Drying over magnesium sulfate was followed by evaporation to dryness. 476 mg of the desired guanidine were obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.ClCCl>C(Cl)(Cl)(Cl)Cl>[CH3:7][C:6]1([CH3:8])[CH2:5][C:4]2([CH3:10])[CH:3]([CH:13]3[CH:12]2[O:11][CH2:16][CH2:15][CH2:14]3)[C:2](=[O:1])[CH2:9]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: C1=COCCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(=O)C2C3CCCOC3C2(C)C1

Procedure:
To a 5-liter round bottomed flask equipped with a quartz immersion well and nitrogen bubbler was added, under nitrogen, 138 g. (1.0 mol.) of isophorone and 498 g. (5.93 mol.) of 3,4-dihydropyran. Enough dichloromethane was added to fill the flask. The solution was bubbled with nitrogen for 1.5 hours and was irradiated with a 450 watt Hanovia medium pressure mercury arc through a Corning 9700 glass filter for 20.5 hours. When the photolysis was completed, the solution was concentrated in vacuo to yield 107.9 g. (0.486 mol.) of a crystalline solid and 80.6 g. of a liquid (0.363 mol.) (Total yield 0.849 mol., 85%). The solid after sublimation and recrystallization had m.p. 111°-112.2° C. IR: 1690 cm-1NMR: (CCl4) 0.92δ (S-3H), 1.12δ (S-3H); 1.32δ (S-3H); 1.35-2.15δ (multiplets 8H); 2.35δ (triplet-2H, J=14Hz); 2.65-2.93δ (M-1H); 3.38-4.20δ (M-2H). The liquid, which had b.p. 101° C./0.3 mm.Hg. was found by glpc to consist of a lower boiling minor component, the solid and a higher boiling product. Redistillation of this fraction gave a fraction, b.p. 85°-90° C./0.1 mm.Hg. which had a NMR (CCl4) spectrum which had methyl singlets at 0.92δ, 1.03δ, 1.10δ and 1.30δ. The singlet at 1.30δ belonged to the solid component, which made up 34% of the mixture. IR: 1695 cm-1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1.C(=O)([O-])O.[Na+]>CS(C)=O>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccnc1Cl
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cccnc1N1CCNCC1
Temperature: 110 °C
Reaction time: 60 h

Procedure:
Piperazine (15 g, 174 mmol) was dissolved in dimethyl sulphoxide (309 g) and to this was added 2,3-dichloropyridine (23.4 g, 158 mmol). The reaction mixture was stirred for 60 h at 110° C. Portions of saturated aqueous sodium hydrogencarbonate solution (overall 250 ml) were added to the reaction mixture and the precipitate produced was drawn off. The filtrate was extracted several times with ethyl acetate (150 ml each time) and the cleaned organic phase was dried and the solvent was removed under vacuum. The residue was distilled at 2×10−1 mbar. The product was obtained at an overhead temperature of 95° C. and a bottom temperature of 155° C. Yield: 9.6 g (28% of the theoretical amount).