Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9]OS(C)(=O)=O)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[Na+].[I-:24]>CC(C)=O>[I:24][CH2:9][CH:7]1[NH:8][C:2](=[O:1])[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]1=2
Reactant: [I-]
Reactant: CS(=O)(=O)OCC1NC(=O)c2ccccc2-c2ccccc21
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1NC(CI)c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of methanesulfonic acid 7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepin-5-ylmethyl ester in acetone (5 mL) is added NaI and the mixture is stirred at 50° C. for 18 h. The solvent is removed under reduced pressure and EtOAc is added. The solution is washed sequentially with sodium bisulfite solution, water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(N(CC)CC)C.O>C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc3ncn(Cc4ccccc4)c3c(=O)[nH]2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(O)cc2)nc2ncn(Cc3ccccc3)c12
Temperature: 100 °C
Reaction time: 58.5 h
Yield: 39.2 %

Procedure:
1.52 g (4.57 mmol) of 7-benzyl-2-(4-methoxyphenyl) hypoxanthine prepared by the same method as in Example 14 was dissolved in 25 ml of acetic acid. After the addition of 3 ml of hydrobromic acid, the mixture was stirred for 58.5 hours at 100° C. After cooling, 10 ml of triethylamine and 100 ml of distilled water were added to the reaction mixture. The crystals produced were separated by filtration and washed with distilled water and ethanol to obtain 0.57 g of 7-benzyl-2-(4-hydroxyphenyl)hypoxanthine (yield 39%).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:7][C:2]1[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: COc1ccccc1Br
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccccc1Nc1ccccc1-c1ccccc1
Temperature: 110 °C
Yield: 82.1 %

Procedure:
Trisdibenzylideneacetonedipalladium (0.276 g, 0.3 mmol) and tri-tert-butylphosphine (0.121 g, 0.6 mmol) were put into a flask, and then dissolved in 40 mL of toluene. Subsequently, 2-biphenylamine (2.53 g, 15 mmol), 1-bromo-2-methoxybenzene (2.81 g, 15 mmol) and tert-butoxy sodium (2.16 g, 22.5 mmol) were added into the flask, and then refluxed at a temperature of 110° C. for 12 hours. After cooling the flask including the reactant mixture to room temperature, the reactant mixture was washed using an ammonium chloride aqueous solution (150 mL) to separate an organic layer. The separated organic layer was washed with distilled water three times, and was then dried with magnesium sulfate. Thereafter, residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and ethylacetate (1:10), and were then recrystallized in normal hexane to produce 3.39 g of N-(2′-methoxyphenyl)biphenyl-2-amine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][CH:23]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:24](O)=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1Cl.[CH2:34](Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:49][C@@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@H:51]1[OH:56].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[OH:56][CH:51]1[CH2:52][CH2:53][CH2:54][CH2:55][CH:50]1[NH:49][C:24](=[O:25])[CH:23]([C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)[CH2:22][C:11]1[CH:10]=[C:9]([C:4]2[CH:3]=[CH:2][C:7]([CH3:34])=[CH:6][CH:5]=2)[N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:12]=1
Reactant: COc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: ClCCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nc(CC(C(=O)NC3CCCCC3O)c3cccc(C)c3)cc2-c2ccc(C)cc2)cc1
Reaction time: 24 h
Yield: 33.2 %

Procedure:
To a solution of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid (product of Method 2) (100 mg, 0.23 mmol), EDC (65 mg, 0.35 mmol), and HOBT (46 mg, 0.34 mmol) in DMF (4.0 mL) was added trans-2-aminocyclohexanol hydrochloride (52 mg, 0.34 mmol) and DIEA (0.20 mL, 1.2 mmol). The reaction mixture was stirred for 24 h, diluted with EtOAc, and washed with 1.0 N NaOH (2×25 mL), water (1×25 mL), 5% formic acid (2×25 mL), water (1×25 mL) and brine (1×25 mL). The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure. Reversed-phase HPLC afforded 40 mg (33%) of N-(2-hydroxy-cyclohexyl)-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionamide as a mixture of diastereomers. HPLC: Rt=3.17 (Method B). MS (ES+): mass calculated for C33H37N3O3, 523.28; m/z found 524.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.92-7.85 (m, 1H), 7.26-7.10 (m, 6H), 7.05-7.01 (m, 3H), 6.94-6.91 (m, 2H), 6.32 (s, 0.5H), 6.29 (s, 0.5H), 4.42 (d, J=4.7 Hz, 0.5H), 4.34 (d, J=5.4 Hz, 0.5H), 3.90 (ddd, J=5.4, 9.4, 20.3 Hz, 1H), 3.76 (s, 3H), 3.24 (m, 0.5H), 3.17 (m, 0.5H), 2.85 (m, 1H), 2.30 (s, 1.5H), 2.28 (s, 1.5H), 2.27 (s, 3H), 1.75 (m, 1H), 1.55 (m, 2H), 1.13 (m, 4H), 0.97 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([CH:8](F)F)/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:21]=1>ClCCl.CN(C=O)C>[F:11][C:2]([F:1])([CH3:8])/[CH:3]=[CH:4]/[C:5]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:21]=[C:20]([CH3:19])[O:24][N:23]=2)[CH2:26][CH2:27]1)=[O:7]
Reactant: O=C(O)/C=C/C(F)(F)C(F)F
Reactant: Cc1nc(N2CCNCC2)no1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(N2CCN(C(=O)/C=C/C(C)(F)F)CC2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
(E)-4,4,5,5-Tetrafluoropent-2-enoic acid (31 mg, 0.23 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.23 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 5-methyl-3-piperazin-1-yl-1,2,4-oxadiazole hydrochloride (25 mg, 0.122 mmol) in dichloromethane (2 ml) and the resulting mixture was stirred at room temperature for three hours. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 24.3 mg of a solid (0.083 mmol, 69%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:14]([CH:16]([CH3:18])[CH3:17])=[N:15][C:11]=2[CH2:10][CH2:9][CH2:8]1)(=O)=O.[C-:27]#[N:28].[Na+]>CS(C)=O.O.C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:13]2[C:12]3[CH:7]([CH2:6][C:27]#[N:28])[CH2:8][CH2:9][CH2:10][C:11]=3[N:15]=[C:14]2[CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=1
Reactant: [C-]#N
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(COS(C)(=O)=O)CCC2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC#N)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Intermediate 41 (3.8 g) and sodium cyanide (1.41 g) was dissolved in dimethyl sulfoxide (20 mL) and the mixture was stirred at 60° overnight. The reaction was stopped (only 1 g nitrile required) and cooled to RT before diluting with water/DCM. The aqueous was further extracted with DCM, and the combined organic extracts were passed though a hydrophobic frit, reduced in volume in vacuo, and the residue purified by flash column chromatography (0-15% MeOH in DCM, silica, repeated chromatography required). The appropriate fractions were combined to give the title compound (1.57 g).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C:5]1([CH3:12])[CH3:11].Cl>O1CCCC1>[CH:3]([CH:4]1[C:5]([CH3:12])([CH3:11])[CH2:6][CH2:7][C:8]1([CH3:10])[CH3:9])=[O:2]
Reactant: COC=C1C(C)(C)CCC1(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)C1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
10 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl ether was dissolved in 100 ml of tetrahydrofuran, and 50 ml of 6N-hydrochloric acid was added thereto. The mixture was vigorously stirred at room temperature for 3 hours, and then treated in the same manner as in Example 11 to obtain 8.60 g of 1-formyl-2,2,5,5-tetramethylcyclopentane. Yield 94%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](/[C:8](=[C:11](/OC)\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](/[C:8](=[C:11](/[NH:21][CH2:17][CH2:18][CH2:19][CH3:20])\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1
Product: CCCCN/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
A sample of 2.5 g. of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile is dissolved in 10 ml. of n-butylamine. The solution is sealed in a stainless steel bomb and heated on a steam bath overnight. The bomb is then opened and the solvent evaporated under reduced pressure. A greenish oil is obtained which is distilled on a Kugelrohr apparatus at 200° C./0.1 mm. to obtain the yellow oily product.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.F[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:17]([N:18]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:3])[C:16]1[CH:19]=[CH:20][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
A heterogeneous mixture of methyl 2-oxo-2H-pyran-3-carboxylate (Aldrich, 2.0 g, 13 mmol, 1.0 eq) and 4-fluorobenzylamine (1.5 mL, 13 mmol, 1.0 eq) in DMF (10 ml) were stirred at room temperature for 3 h. The reaction mixture was treated with EDCI (3.4 g, 18 mmol, 1.4 eq) and DMAP (0.11 g, 9.91 mmol, 0.07 eq) at room temperature and the resulting solution was stirred for 12 h. The reaction mixture was quenched with 1N aqueous HCl and the solution was extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with 10% aqueous LiCl (3×70 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo to afford the product (2.5 g, 73%) as a solid, that was used without further purification. 1H NMR (DMSO-d6) δ 8.17-8.20 (m, 1H), 8.03-8.05 (m, 1H), 7.38-7.46 (m, 2H), 7.16-7.22 (m, 2H), 6.37 (dd, 1H, J=6.94 Hz), 5.13 (s, 2H), 3.73 (s, 3H); HRMS (ESI+), Calcd.: 262.0879. found: 262.0885.
Reaction SMILES: [C:1](=[O:20])([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[Na+].[I-:22]>CC#N>[C:1](=[O:20])([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][I:22]
Reactant: O=C(OCCCCCl)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCCCCI)Oc1c(F)c(F)c(F)c(F)c1F
Yield: 89.7 %

Procedure:
A mixture of 4-chlorobutyl pentafluorophenyl carbonate (1.69 g, 5.3 mmol) and NaI (7.99 g, 53.3 mmol) in CH3CN (20 ml) was refluxed under nitrogen for 960 minutes. Then the solvent was evaporated and the residue taken up with CH2Cl2 and washed with water (2×50 ml). The organic phase was then dried and evaporated yielding 4-iodobutyl pentafluorophenyl carbonate (1.95 g, 90%) as a yellow oil that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=1.[P:37]([O-:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40].CN1[CH2:51][CH2:50][O:49]CC1>CC#N.[NH4+].[Cl-]>[CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([P:37]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:44])=[C:8]([P:37]([O:49][CH2:50][CH3:51])([O:38][CH2:39][CH3:40])=[O:41])[CH:7]=1
Reactant: CCOP([O-])OCC
Reactant: CN1CCOCC1
Reactant: COC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1P(=O)(OCC)OCC
Temperature: 95 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
To 3-(3,4-Bis-trifluoromethanesulfonyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (2 g, 3.47 mmol), diethyl phosphite (1 mL, 7.65 mmol) and 4-methyl morpholine (0.93 mL, 8.3 mmol) in MeCN (10 ml) was added Pd(Ph3)4 (167 mg, 0.15 mmol). The mixture was allowed to stirred for two days at 95° C. then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was dried over magnessium sulfate, concentrated, and chromatographed over silica gel (5% MeOH/EtOAc) to an oil (0.2 g 37% yield). MS [M+H]+ 552 and [M+Na] 574.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11][C:12]1([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4].CO[C:38](OC)([CH3:40])[CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@@H:9]1[O:33][C:38]([CH3:40])([CH3:39])[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:10]1[CH2:11][C:12]1([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1(CCOCc2ccccc2)CC1)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1(CCOCc2ccccc2)CC1

Procedure:
The 5(S)-tert-butoxycarbonylamino-6-[1-(2-benzyloxyethyl)cyclopropyl]-4(S)-hydroxy-2(R)-methyl-hexanoic acid (N-butyl)amide thus obtained is reacted with dimethoxypropane and p-toluenesulfonic acid hydrate in a manner analogous to that described in Example 1 d) and the product is purified by means of FC over 80 g of silica gel (mobile phase C). This gives the title compound as the pure diastereomer: Rf (A)=0.58,
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:8]([C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=3)[NH:9][C:10](=[O:24])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:12]=2[CH3:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C)C=O>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH:8]2[N:9]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10](=[O:24])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)[C:12]([CH3:13])=[C:7]2[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:32][CH:31]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1=C(C(=O)C2CCC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C(=O)C2CCC2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 4-{5-(cyclobutylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 20) (29 mg, 0.066 mmol) and potassium carbonate (16.4 mg, 0.12 mmol) in dimethylformamide (1 ml) is treated with tert.-butyl bromoacetate (14.2 mg, 0.073 mmol), and then stirred at room temperature overnight (16 h). The reaction solution is quenched with water (3 ml) and extracted with diethyl ether (2×5 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([O-])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[K+].P(Cl)(Cl)(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([S:12]([Cl:21])(=[O:14])=[O:13])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1S(=O)(=O)Cl
Yield: 88.5 %

Procedure:
Sixty grams of potassium 4-chloro-3,5-dinitro-o-toluenesulfonate, 70 grams of phosphorus pentachloride and 120 ml. of phosphorus oxychloride are mixed and refluxed for 3 hours. The mixture is filtered to remove some insoluble solid. The filtrate is carefully poured into water at 20° C. to 30° C. The precipitated solid is collected and dissolved in 500 ml. of benzene. The benzene solution is washed with water and then dried over MgSO4. After removing the magnesium sulfate, the benzene is concentrated to 100 ml. and 400 ml. of hexane added. The precipitated solid is collected and recrystallized from 300 ml. hexane and 100 ml. of benzene to yield 50 grams of solid with melting point 105° C. to 107° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[Na+].[I-].[NH2:12][OH:13].[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:14]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:13][N:12]2[C:6]([C:5]([CH3:9])([CH3:8])[O:4][CH2:3][CH2:2]2)=[N:7]1)[CH3:20]
Reactant: CC(C)(C#N)OCCCl
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NO
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C(=O)OCC)N=C2N(CCOC2(C)C)O1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a stirred solution of intermediate 23, 2-(2-chloroethoxy)-2-methylpropanenitrile (14.7 g, 0.10 mole) and NaI (1.5 g, 10 mmol) in ethanol (50 mL) was added an aqueous solution (50%) of hydroxylamine (18.4 g, 0.30 mole) resulting in an exothermic reaction. Following this the reaction mixture was heated at 80° C. for 2 h. Upon cooling to room temperature the solvent was removed. The resulting residue was dissolved in 1:1 ethanol/H2O (100 mL) and cooled in an ice bath. To this was added diethyl acetylenedicarboxylate (17.6 mL, 0.110 mole) over 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Following this, it was diluted with ethyl acetate (250 mL), washed with H2O (2×100 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give the crude product as a yellow oil. Flash chromatography on a silica gel column, eluting with 20-40% ethyl acetate/Hexanes, provided the title compound as a viscous pale yellow oil (15.29 g, 48.6% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 4.35-4.28 (2H, m), 4.18-4.12 (2H, m), 3.60-3.56 (1H, m), 3.51-3.47 (1H, m), 3.30 (1H, d, J=16.2 Hz), 2.94 (1H, d, J=16.2 Hz), 1.52 (3H, s), 1.51 (3H, s), 1.29 (3H, t, J=7.0 Hz), 1.24 (3H, t, J=7.0 Hz). LCMS (M+H) calcd for C14H23N2O7: 315.16; found: 315.33.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.Cl.[OH-].[K+]>>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[CH:10][C:11]1[S:12][C:13]2[CH:7]=[CH:8][CH:2]=[CH:1][C:14]=2[N:15]=1
Reactant: Cc1nccs1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Oc1ccccc1C=Cc1nc2ccccc2s1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
Salicylaldehyde (6.1 g) and 2-methylthiazole (7.5 g) were mixed and conc. hydrochloric acid (1.5 ml) was added thereto. The mixture was stirred with heating at 100° C. for 9 hr. The reaction mixture was cooled, and aqueous potassium hydroxide solution was added. The aqueous layer was washed with ether and made acidic with hydrochloric acid and extracted again with ethyl acetate. The organic solvent was dried and concentrated to give the title compound (2.5 g) as pale-yellow crystals, melting point 235-236° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][C:13]1([CH:17]=[O:18])[CH2:16][O:15][CH2:14]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[O:8][C:9]([CH:17]([C:13]2([CH3:12])[CH2:16][O:15][CH2:14]2)[OH:18])=[CH:10][CH:11]=1
Reactant: Cc1ccco1
Reactant: CC1(C=O)COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C2(C)COC2)o1
Temperature: -70 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
12.0 ml (30 mmol, 1.7 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 2.46 g (30 mmol, 1.7 eq) of 2-methylfuran in 50 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 3 hours. The reaction medium was cooled to −70° C. and then 2.17 g (18 mmol, 1 eq) of 3-methyloxetane-3-carbaldehyde at 83% were added. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. 3.02 g of (5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methanol were obtained in the form of an orange oil. Yield=92%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=O.[N:18]1[C:23](C)=[CH:22][CH:21]=[CH:20][C:19]=1C>CN1CCN(C)C1=O.CCOC(C)=O>[CH2:10]([NH:12][C:13]([NH:15][C:16]1[N:1]=[C:2]2[CH:7]=[C:6]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[CH:5]=[CH:4][N:3]2[CH:17]=1)=[O:14])[CH3:9]
Reactant: Cc1cccc(C)n1
Reactant: CCNC(=O)NC(=O)CCl
Reactant: Nc1ccccn1
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: CCNC(=O)Nc1cn2ccc(-c3cccnc3)cc2n1
Yield: 0.1 %

Procedure:
A solution of aminopyridine (3) (0.73 g, 4.26 mmol), N-(chloroacetyl)-N′-ethylurea (0.84 g, 5.10 mmol) and 2,6-lutidine (0.59 mL, 5.10 mmol) in 1,3-dimethyl-2-imidazolidinone (7 mL) was warmed under nitrogen at 110° C. for 5 hours. The mixture was diluted with EtOAc and washed with water (6×), then adsorbed onto silica by removal of solvent in vacuo. Silica gel chromatography (EtOAc gradient to MeOH/EtOAc (2:23)) provided the product (0.76 mg, 6%) as a solid, mp 290-294° C. (decomposed).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]([O:24]C)=[O:23])=[N:14]1.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[N:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]([OH:24])=[O:23])=[N:14]1
Reactant: COC(=O)c1nn(-c2ccc(OC(F)(F)F)cc2F)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(OC(F)(F)F)cc2F)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of methyl 1-[2-fluoro-4-(trifluoromethoxy)phenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (3.4 g, 9.3 mmol) in THF (150 mL) was added 1 M NaOH aqueous solution (14 mL, 14 mmol), and the mixture was stirred at room temperature for 30 min. The mixture was acidified with 1 M HCl aqueous solution and concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.2 g, 97% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.88 (3H, s), 7.52-7.59 (1H, m), 7.86 (1H, dd, J=10.8, 2.5 Hz), 7.97 (1H, t, J=8.7 Hz), 8.91 (1H, d, J=1.1 Hz), 14.83 (1H, brs).