Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC#N>CCOCC>[CH:14]1([O:13][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=2[O:11][CH3:12])[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COc1ccc(C(=O)N(C)OC)cc1OC1CCCC1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(C(=O)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
To an ice bath cooled stirred solution of N-methoxy-N-methyl-3-cyclopentoxy-4-methoxybenzamide (1.2 g, 4.3 mmol) in 15 mL of anhydrous ether was added a 3 M solution of phenylmagnesium bromide (3.6 mL, 10.8 mmol) in ether dropwise over a 20 minute period. A white gum precipitated from the mixture and dry THF (6 mL) was added to facilitate stirring. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction was then quenched at 0° C. with a saturated aqueous solution of ammonium chloride (8 mL). The resulting mixture was allowed to warm to room temperature and was diluted with ethyl acetate (10 mL). The organic layer was separated and sequentially washed with 1 N citric acid (2×10 mL), saturated NaHCO3(aq) (2×10 mL), and brine (2×10 mL). The organic layer was then dried over MgSO4, filtered and concentrated in vacuo to give a viscous oil. The crude product was purified by flash column chromatography (silica gel, methylene chloride) and the resulting product was then dried in vacuo (40° C., <1 mmHg) to afford 0.75 g (60%) of a slightly impure product as a white solid: mp 73.5-75.0° C.; 1H NMR (CDCl3) δ 7.80-7.72 (m, 2H), 7.63-7.15 (m, 5H), 6.94-6.79 (m, 1H), 4.91-4.78 (m, 1H), 3.92 (s, 3H), 2.09-1.50 (m, 8H) also some impurity in the aromatic region; 13C NMR (CDCl3) δ 195.7, 153.9, 147.5, 138.3, 131.8, 129.7, 128.1, 125.1, 120.3, 115.5, 110.3, 80.5, 56.1, 32.7, 24.1; HPLC (Waters Nova-Pak/C18 column, 3.9×150mrn, 4 micron, 1 mL/min, 60/40, CH3CN/0.1% H3PO4(aq)) 6.2, min 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[N:10][C:11]=3[CH3:24])[CH:16]=2)=[O:22])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: NN1CCOCC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCOCC2)n(C)n1
Yield: 81 %

Procedure:
As described for example 3, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (86 mg, 81%) which was obtained as a white solid. MS: m/e=416.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:14])[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1.C(O)(=O)C1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:14])[C:9]([N+:11]([O-:23])([CH3:12])[CH3:13])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)C(=O)C(O)c1cncc(Br)c1
Agent: O=C(O)c1ccccc1
Solvent: ClCCl
Product: C[N+](C)([O-])C(=O)C(O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
A solution of 2-(5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (100 mg, 0.387 mmol) in DCM (3.0 mL) was cooled in an ice water bath and treated with mCPBA (100.3 mg, 0.581 mmol). After stirring at room temperature for 4 h, the mixture was cooled and additional mCPBA was added (66.7 mg, 1 eq.). After stirring 18 h at room temperature, another 0.3 eq of mCPBA was added (13.3 mg). Finally after 4 h, the reaction was quenched by addition of 38% aqueous sodium bisulfite (100 uL) and the mixture was dried over Na2SO4. After filtration, MP—CO3 (1.74 mmol) was added to scavenge the benzoic acid by-product. After 5 d (3 hours is sufficient), the mixture was filtered and the resin was rinsed with 10% MeOH in DCM. The product was concentrated in vacuo to afford 2-(5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide N-oxide (97.0 mg, 91.7%). MS: m/z 275 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][CH3:25])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2NC1C=CC(C)=C(O)C=1)=[O:5])[CH3:2].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][CH3:25])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:26][C:27]1[CH:32]=[N:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc(C)c(O)c3)c2c1OC
Reactant: COc1ccc(N)cn1
Solvent: CC#N
Product: CCOC(=O)c1cn2ncnc(Nc3ccc(OC)nc3)c2c1OC
Yield: 36.4 %

Procedure:
Compound G of Example 96 (0.1 mmol) and 5-amino-2-methoxypyridine (62 mg, 0.5 mmol) in CH3CN (0.5 mL) was stirred for 2 hrs. The crude mixture was purified by preparative HPLC. The desired material was collected, concentrated, and neutralized with aqueous NaHCO3. The solid was collected, washed with water, and dried to provide 12.5 mg (36%) of red solid. MS: [M+H]+=344; 1H NMR (CDCl3): δ 8.30 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.78 (d, J=7.9 Hz, 2H), 6.77 (d, J=8.8 Hz, 1H), 4.30 (q, J=7.0 Hz, 2H), 4.11 (s, 3H), 3.89 (s, 3H), 1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][O:9][CH2:8][O:7][C@@H:6]1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[N+:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23])([O-])=O.CO.N>[Pd].C1COCC1>[C:1]([C@@H:5]1[CH2:10][O:9][CH2:8][O:7][C@@H:6]1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3].[NH2:13][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23]
Reactant: O=C([O-])CCCCCC[N+](=O)[O-]
Agent: [Pd]
Agent: CO[C@H]1OCOC[C@H]1C(C)(C)C
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NCCCCCCC(=O)[O-]

Procedure:
5 g (18.2 mmol) of the cis-t-butyl-2-methoxy-3,5-dioxane-7-nitro-heptanoate obtained in Example 1 was added to a mixture solvent of 50 mL of MeOH and 50 mL of THF saturated with ammonia. Hydrogenation was performed for 6 hours at room temperature in the presence of 10% Pd/C catalyst. 4.43 g (88.6%) of the target compound was obtained as colorless oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:7])=[O:3].[NH2:17][NH2:18]>C(Cl)Cl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]([CH3:7])[CH2:5][O:4][C:2]([NH:17][NH2:18])=[O:3])([O-:16])=[O:15]
Reactant: NN
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(COC(=O)NN)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
A solution of 2-(2-nitrophenyl)propyl chloroformate (6.0 g, 24.6 mmol) in methylene chloride (20 mL) was added dropwise to a solution of hydrazine (3.0 mL, 98 mmol) in methylene chloride (50 mL) over a period of 30 min. The reaction mixture was stirred at room temperature for an additional 15 min. The solvent was evaporated to afford light brown oil. The residue was purified on a silica gel column. Elution of the column with 20% ethyl acetate in hexanes gave 3.35 g (14 mmol, 57% yield) of 2-(2-nitrophenyl)propoxycarbonyl hydrazine. 1H-NMR (600 MHz, DMSO-d6): δ 8.10 (s, 2H, CONH), 7.82 (d, J=7.5 Hz, 1 H, Ar—H), 7.67 (m, 2 H, Ar—H); 7.47 (m, 1 H, Ar—H), 4.15 (d, J=7.2 H, 2 H, CH2), 3.9 (s, 2 H, NH2), 3.39 (m, 1 H, CH), 1.25 (d, J=6.9 Hz, 3 H, CH3). 13C-NMR (150 MHz, DMSO-d6): δ 157.99 (OCOR), 150.00 (C ipso to NO2), 136.72 (C ipso to CH(CH3)CH2OCOR), 132.86 (C para to NO2), 128.55 (C para to CH(CH3)CH2OCOR), 127.69 (C ortho to CH(CH3)CH2OCOR), 123.68 (C ortho to NO2), 67.49 (CH2OCOR), 33.36 (CH), 17.93 (CH3). Mass analysis (MALDI-TOF): calculated for C10H13N3O4 239.23, found 239.20 (C10H13N3O4Na 262.18 is the major peak). TLC: 5% metaniol in chloroform, Rf=0.5.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:27])=[C:24]([C:37]([OH:40])([CH3:39])[CH3:38])[N:23]=[C:22]2[CH2:41][O:42][CH2:43][CH3:44])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])=[O:27])=[C:24]([C:37]([OH:40])([CH3:38])[CH3:39])[N:23]=[C:22]2[CH2:41][O:42][CH2:43][CH3:44])=[CH:16][CH:15]=1)([OH:7])=[O:5]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 96(b) but using 396 mg of pivaloyloxymethyl 1-{4-[2-(t-butoxycarbonyl)phenyl]phenyl}methyl-2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in step (a) above], 312 mg of the hydrochloride of the title compound were obtained as an amorphous powder, melting at 65° C. (with softening).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=1)[C:10](=[O:19])[C:11]([C:14]1[NH:18][N:17]=[N:16][N:15]=1)=[CH:12][N:13]=2)[CH2:2][CH2:3][CH3:4].[C:21]([C:23](=CNC1C=CC(C2C=CC=CC=2)=CN=1)C(OCC)=O)#N>>[C:1]1([C:5]2[CH:6]=[CH:7][C:8]3[N:9]([CH:20]=2)[C:10](=[O:19])[C:11]([C:14]2[NH:15][N:16]=[N:17][N:18]=2)=[CH:12][N:13]=3)[CH:23]=[CH:21][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C#N)=CNc1ccc(-c2ccccc2)cn1
Reactant: CCCCc1ccc2ncc(-c3nnn[nH]3)c(=O)n2c1
Product: O=c1c(-c2nnn[nH]2)cnc2ccc(-c3ccccc3)cn12
Yield: 31 %

Procedure:
In a manner similar to that described for the preparation of 7-n-butyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 7, the title compound (m.p. 308°-309° decomp) was prepared in 31% yield from ethyl 2-cyano-3-(5-phenyl-2-pyridylamino)acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Nc1cc(F)c(Cl)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OC(c1nc2cc(Cl)c(F)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4-Chloro-5-fluoro-benzene-1,2-diamine (5.20 g; 32.4 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (7.00 g; 48.6 mmoles) were suspended in 6N HCl (9 mL; 54 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (100 mL) and with ethyl acetate (100 mL), then sodium bicarbonate (6.90 g; 81.00 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×40 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:22]([O:13][C:12]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1])[CH:7]=[CH:8][CH:9]=1)=[O:14])[CH3:23]
Reactant: CCI
Reactant: O=C(O)c1cccc2cccc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8-bromo-naphthalene-1-carboxylic acid (1.6 g) in DMF (15 ml) was treated with potassium carbonate (2.2 g) and iodoethane (1.03 ml). The reaction mixture was stirred overnight at r.t., then quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give 8-bromo-naphthalene-1-carboxylic acid ethyl ester (1.57 g) as colorless liquid. MS (ISP): 279.1 ((M+H)+.).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27]O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:31])=O.C(=O)([O-])O.[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][Cl:31])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CSc4ccccc4CO)ccc3o2)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(CSc4ccccc4CCl)ccc3o2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 136.2 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-hydroxymethylphenylthiomethyl)benzofuran-2-yl]thiazole (0.42 g), thionyl chloride (0.1 g) and N,N-dimethylformamide (3 drops) in chloroform (5 ml) was stirred for 3 hours at ambient temperature. The resulting mixture was poured into aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-tert-butyl-2-[5-(2-chloromethylphenylthiomethyl)benzofuran-2-yl]thiazole (0.49 g).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]([CH:45]=[CH:46][CH:47]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([C:40]([O:42]CC)=[O:41])[N:39]=2)[N:36]=1>CN1CCCC1=O.C(OCC)(=O)C.CN(C)C=O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:26][C:27]1[CH:28]=[C:29]([CH:45]=[CH:46][CH:47]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([C:40]([OH:42])=[O:41])[N:39]=2)[N:36]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: CCOC(=O)c1cn2nc(Oc3cccc(N)c3)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(C(=O)O)cn4n3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.3 %

Procedure:
To a mixture of 3-(1-cyano-1-methylethyl)benzoic acid (454 mg, 2.40 mmol), tetrahydrofuran (10 mL) and N,N-dimethylformamide (0.01 mL) was added oxalyl chloride (366 mg, 2.88 mmol), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, tetrahydrofuran was added to the residue, and the mixture was azeotroped twice. The residue was dissolved in N-methylpyrrolidone (4 mL), added to a solution of ethyl 6-(3-aminophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate (350 mg, 1.17 mmol) in N-methylpyrrolidone (6 mL), and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. To the residue were added 8N aqueous sodium hydroxide solution (4.0 mL) and methanol (10.0 mL), and the mixture was stirred at room temperature for 10 min. 6N Hydrochloric acid (5.0 mL) and water (60 mL) were added to the mixture, and the mixture was extracted with ethyl acetate (150 mL). The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane to give the title compound (828 mg, 94%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[OH:12])=[C:4]([F:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:4]([F:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)c(C(O)C2CCCC2)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Product: COc1ncc(Br)c(C(=O)C2CCCC2)c1F
Reaction time: 3 h
Yield: 103 %

Procedure:
To a solution of (5-bromo-3-fluoro-2-methoxypyridin-4-yl)(cyclopentyl)methanol (430 mg) in acetonitrile (10 mL) was added Dess-Martin reagent (720 mg) at room temperature, and the mixture was stirred for 3 hr, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (440 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:37])([F:36])[C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:33]([C:30]3([C:29]([F:37])([F:36])[F:28])[CH2:32][CH2:31]3)=[O:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3(C(F)(F)F)CC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=415.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:11]=1[CH3:10]
Reactant: Cc1c(N)cccc1Cl
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: Cc1c(Cl)cccc1N=Cc1ccccc1O
Reaction time: 0.25 h

Procedure:
o-Hydroxybenzaldehyde (0.20 mole) was treated with 2-methyl-3-chloroaniline (0.20 mole) with vigorous stirring in a 1 liter Erlenmeyer flask. After 15 mins., 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 45 mins. The reaction mixture was left standing at room temperature for 10 min., then it was placed in an ice-bath for 0.5 hour. The crystals which formed were collected, washed with 95% ethanol, and air dried. Recrystallization from 85% ethanol gave N-(o-hydroxybenzylidene)-2-methyl-3-chloroaniline. m.p. 95°-97° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccc(F)cc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)NC1CCc2ccc(F)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step E by the procedure described in Example 1, Step F. 1H NMR (300 MHz, CDCl3): 1.35 (s,6H), 1.41 (s,9H), 1.93 (m,1H), 2.4-2.9 (m,5H), 4.54 (m,1H), 5.19 (br s,1H), 6.73 (m,2H), 6.88 (dt;2,8 Hz;1H), 7.19 (dd;6,8 Hz;1H), 8.07 (m,1H). FAB-MS: calculated for C20H28FN3O4 393; found 394 (M+H,56%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.Br[CH2:27][C:28](=[O:38])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.O>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][C:28](=[O:38])[CH2:27][N:3]2[C:2]([CH3:1])=[CH:6][N:5]=[CH:4]2)=[CH:32][CH:33]=1
Reactant: O=C(CBr)CCc1ccc(Cl)cc1
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O
Solvent: CC#N
Product: Cc1cncn1CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixture of 4-methyl-1-tritylimidazole (12.9 g, 39.8 mmol) and 1-bromo-4-(4-chlorophenyl)butan-2-one (12.5 g, 47.8 mmol, 1.2 equivalents) in CH3CN (~200 mL) was heated at reflux for 16 hours. The reaction mixture was then cooled to room temperature and 2N HCL (30 mL) was added. The reaction mixture was then heated at reflux for 30 minutes, cooled to room temperature and treated with water (~500 mL). The resulting mixture was then washed with ether (~1×100 mL) and the pH adjusted to between 9 and 10 with 2N NaOH. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined extracts were then washed with brine and dried over Na2SO4. After filtration and concentration, the resulting crude product (8.5 g) was purified by silica gel chromotography, eluting with 1-8% methanol in methylene chloride to give 8.2 g of 4-(4-chlorophenyl)-1-(5-methylimidazol-1-yl)butan-2-one (70% yield). The hydrochloride salt was recrystallized from methanol/ethyl acetate with m.p. 227°-228° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](F)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[CH3:22][S-:23].[Na+].C[S-].O>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([S:23][CH3:22])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(-c2cc(C(C)C)nc(N)n2)c2ccccc12
Reaction time: 2 h
Yield: 98 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.281 g) was dissolved in dimethyl sulphoxide (DMSO) (10 mL) and sodium thiomethoxide (0.070 g) was added. The reaction mixture was stirred at room temperature for 2 hours at which time another equivalent of thiomethoxide was added and the reaction stirred for another 2 hours. The mixture was poured into water (100 mL) and the product was extracted into ethyl acetate/hexane (3×50 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The reaction product was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate to give 2-amino-4-(4-methylthionaphth-1-yl)-6-isopropylpyrimidine (0.303 g), m.p. 139°-140° C.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH3:30][CH:31]([CH3:36])[CH2:32][CH2:33]C=O>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:33][CH2:32][CH:31]([CH3:36])[CH3:30])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Reactant: CC(C)CCC=O
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCC(C)C

Procedure:
The product of Example 100 is treated with 4-methylpentanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH3:10][N:11]=[C:12]=[O:13]>C(OC(C)C)(C)C>[CH3:10][NH:11][C:12]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:13]
Reactant: CN=C=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CC(C)OC(C)C
Product: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
A mixture of 27.4 g of 3,4-dichloroaniline in 140 ml of isopropyl ether was added slowly to 9 g of methyl isocyanate in 100 ml of isopropyl ether and the mixture was refluxed for 2 hours and was then cooled to 0° C. The precipitate formed was recovered by vacuum filtration and was washed with isopropyl ether. The mother liquors were concentrated to obtain a second crop. The two combined crops weighing 19.5 g and melting at 156° C. were crystallized from ethyl acetate to obtain N-methyl-N'-(3,4-dichlorophenyl)-urea melting at 160° C., identical to the product described by Onley et al., J. Ass. Off. Anal. Chem., Vol. 52 (1969), p. 545.