Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C@@H:5]1[C@:13]2([CH3:14])[C@@:8]([OH:29])([CH2:9][C@@H:10]([C:15]3[CH:20]=[C:19](C)[C:18](C(C)(C)C)=[C:17](C)[C:16]=3O[SiH3])[CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[O:30]1CCOCC1>O=[Mn]=O>[CH:2](/[CH:3]=[CH:4]/[C@@H:5]1[C@:13]2([CH3:14])[C@@:8]([OH:29])([CH2:9][C@@H:10]([C:15]3[CH:20]=[CH:19][C:18]([OH:30])=[CH:17][CH:16]=3)[CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:1]
Reactant: Cc1cc([C@H]2CC[C@]3(C)[C@@H](/C=C/CO)CC[C@]3(O)C2)c(O[SiH3])c(C)c1C(C)(C)C
Reactant: C1COCCO1
Agent: O=[Mn]=O
Product: C[C@]12CC[C@H](c3ccc(O)cc3)C[C@@]1(O)CC[C@@H]2/C=C/C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.90 g of (1R,3aS,5S,7aR)-1-[(E)-3-hydroxy-1-propenyl]-5-(4-tert-butyldimethyl-silyloxyphenyl)-7a-methylperhydroinden-3a-ol in 40 ml of dioxane, 13.80 g of MnO2 were added while cooling in an ice bath. The mixture was stirred at room temperature for 1 hr, filtered through celite and the filtrate was made acid to pH 1 with 3N HCl and, using the same procedure described in Prepn, 1, the title compound (II-bb) (2.75 g) was obtained as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[CH2:5]1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][CH:6]2[CH2:7][CH2:8][CH2:9][CH:4]([CH3:3])[CH2:5]2)[N:15]=[CH:14][N:13]=1
Reactant: CC1CCCC(O)C1
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1CCCC(Oc2cc(Cl)ncn2)C1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.14 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.34 g of 3-methylcyclohexanol (mixture of cis-dorm and trans-form) was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes and then cooled to 0° C., to which 1.5 ml of a tetrahydrofuran solution containing 0.4 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.31 g of 4-chloro-6-(3-methylcyclohexyloxy)pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.C(OCC)(=O)C.CCCCCC>CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1
Reactant: Cn1ccnc1N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: Cn1ccnc1N1CCC(c2ccc(N)cc2)CC1

Procedure:
Hydrogenation of the product from part (iii) above (0.50 g) in methanol (30 ml) according to the method of Example 1(ii) gave the title compound, (0.43 g), m.p. 187°-188° from ethyl acetate/hexane.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[Cl:8][C:4]1[N:3]=[C:2]([NH:12][CH:9]2[CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NC1CC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1cncc(NC2CC2)n1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A glass microwave reaction vessel was charged with 2,6-dichloropyrazine (1.0 g, 6.71 mmol) and cyclopropanamine (0.383 g, 6.71 mmol) in DMF (4 mL) followed by cesium carbonate (2.187 g, 6.71 mmol). The reaction was stirred and heated in an oil bath at 100° C. for 15 h, then cooled to RT. The mixture was diluted with DCM and washed with H2O. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 5-10% EtOAc in Hex) to give 6-chloro-N-cyclopropylpyrazin-2-amine (0.87 g, 5.13 mmol, 76%) as a yellow solid. MS (ESI, pos. ion) m/z: 170 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CN(C)CCCN=C=NCC.[NH2:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([NH:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[O:33])=[C:30]([O:44][CH3:45])[CH:29]=1>O>[CH2:40]([N:37]([CH2:38][CH3:39])[CH2:36][CH2:35][NH:34][C:32](=[O:33])[C:31]1[CH:42]=[CH:43][C:28]([NH:27][C:10](=[O:12])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:29][C:30]=1[O:44][CH3:45])[CH3:41]
Reactant: O=C(O)COCc1ccccc1
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1OC
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
664 mg (4 mmol) of benzyloxyacetic acid is introduced into 20 ml of methylene chloride, mixed with 768 mg (4 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDG), and stirred for 0.5 hour at 4° C. Then, 1.06 g (4 mmol) of 4-amino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide in a total of 12 ml of methylene chloride is added to the batch and stirred for 48 hours at room temperature. After 30 ml of water is added, it is extracted twice with 30 ml each of methylene chloride. The organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on 20 g of Isolute NH2 (50 μm) with methylene chloride. The correspondingly combined fractions are concentrated by evaporation and chromatographed again on 20 g of Isolute NH2 (50 μm) with a gradient from cyclohexane to cyclohexane:methylene chloride 50:50 as an eluant, and 348 mg (27% of theory) of N-(2-diethylamino-ethyl)-4-(2-benzyloxy-acetylamino)-2-methoxy-benzamide is obtained as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:34]([O:35][CH3:36])=[CH:33][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:34]([O:35][CH3:36])=[CH:33][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][OH:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CCO)CC2
Yield: 42 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. Product was isolated as a white foam (35 mg, 42%). MS (ESI+): 499 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 6.33 (s, 2H), 5.60 (s, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.47 (t, J=8 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 2H), 3.63 (d, 5H), 3.09 (s, 1H), 2.89-2.69 (m, 20H), 2.53 (d, J=9 Hz, 1H), 2.28 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.ClS([N:21]=[C:22]=O)(=O)=O.CN(C=O)C>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:21])=[C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc(-c3cccnc3)[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1c(-c2cccnc2)[nH]c2cc(F)ccc12
Reaction time: 8 h

Procedure:
To a solution of 6-fluoro-2-pyridin-3-yl-1H-indole (Example 89, 212 mg, 1.0 mmol) in dichloromethane (90 mL) at ambient temperature is added chlorosulfonyl isocyanate (0.71 g, 5 mmol) and the mixture is stirred overnight. Anhydrous DMF (1 mL) is added. After 1 h, the solvent is removed in vacuo and the residue purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to give 6-fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 7.12-7.21 (m, 1H), 7.39 (dd, J=9.5, 2.4 Hz, 1H), 7.64-7.74 (m, 2H), 8.27-8.35 (m, 1H), 8.73 (dd, J=4.9, 1.6 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 12.89 (s, 1H). MS (ESI) m/z 238.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][C:3]1=[O:17].[CH2:18]([CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH2:21]1)[CH3:19]>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]([CH2:18][CH3:19])[CH2:21]2)=[CH:4][C:3]1=[O:17]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(=O)n1C
Reactant: CCC1CNc2ccccc21
Product: CCC1CN(c2cc(C)n(C)c(=O)c2)c2ccccc21
Temperature: 150 °C
Yield: 62 %

Procedure:
A mixture of 1,6-dimethyl-4-(trifluoromethanesulphonyloxy)-2-pyridone (1.5 g, 5.5 mM) and 3-ethylindoline (1.22 g, 83 mM) was heated at an external temperature of 150° C. under argon for 3 hours. The solution was cooled. The residue was triturated with acetone to afford a solid which was collected by filtration. This solid was washed with acetone to give 1,6-dimethyl-4-(3-ethylindolin-1-yl)-2-pyridone as the hemi-trifluoromethylsulphonate salt; (1.76 g, 62% yield); m.p. 174°-175° C.; microanalysis, found C, 60.2; H, 6.0: N, 8.0%; C18H21N2. 0.5CF3SO3H requires: C, 60.1; H, 5.9; N, 8.0%: NMR (DMSOd6); 0.9-1.0(3H, t, CH2CH3), 1.4-1.6(1H, m, CHEt), 1.70-1.9(1H, m, CHEt), 2.44(3H, s, CH3), 3.25-3.4(1H, m, indoline H), 3.5(3H, s, +NCH3), 3.6-3.7(1H, m, indoline H), 4.05-4.15(1H, m, indoline H), 6.2(1H, d, pyridine CH), 6.6(1H, d, pyridine CH), 6.9-7.05(1H, t, aromatic), 7.15-7.4(3H, m, aromatic).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22]>CCOCC>[NH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH:22][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN(CCCN)CCCN
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOCC
Product: CN(CCCN)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The reaction was carried out in the dark. A solution of 4-fluoro-3-nitrophenyl azide (0.91 g, 5.0 mmol, Sigma) in 10 ml dry ether was added dropwise with stirring to a solution of 3.2 ml of N-(3-aminopropyl)-N-methyl-1,3-propanediamine (10 mmol, Aldrich) in 20 ml dry ether and the mixture was stirred for 30 min. The reaction was monitored using TLC (alumina, elution with methanol). The solvent was removed and the red oil was dissolved in 25 ml water, 25 ml 1.0M NaOH and then extracted into ethyl acetate (2×50 ml). The organic phase was dried over MgSO4 and the solvent then removed in vacuum. TLC: (I) alumina, eluted with methanol, Rf=0.43 (II) silica gel, elution with 1:9 AcOH/H2O, Rf between Rf=0.23 and Rf=0.55. 1H NMR (CDCl3 /TMS) δ: 1.45 (2H, broad s, NH), 1.64 (2H, m, CH2), 1.87 (2H, p, J=6.52 Hz, CH2), 2.25 (3H, s, CH3), 2.43 (2H, t, CH2), 2.47 (2H, t, J=6.46 Hz, CH2), 2.73 (2H, t, J=6.89 Hz, CH2), 3.37 (2H, m, J=6.61 Hz, CH2), 6.89 (1H, d, J=9.23 Hz, ArH), 7.10 (1H, dd, J=2.73, 9.20 Hz, ArH), 7.79 (1H, d, J=2.74 Hz, ArH), 8.47 (1H, m, NH). 13C NMR (CDCl3 /TMS) δ: 143.23 (Q), 131.24 (Q), 127.91 (CH), 127.16 (Q), 115.73 (CH), 115.44 (CH), 55.70 (CH2), 55.40 (CH2), 42.03 (CH2), 41.90 (CH3), 40.50 (CH2), 30.94 (CH2), 26.20 (CH2).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH2:12])[N:6]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][CH:35]=1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:5]2[N:6]=[C:2]([CH3:1])[N:3]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:4]=2)=[O:42])=[CH:36][CH:35]=1
Reactant: Cc1nc(-c2sccc2N)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(C)n2)cc1

Procedure:
The title compound was prepared from 2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B (540 mg, 57%). Method [7] Retention time 7.42 min by HPLC (MH+ 570).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH:27]1(O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:8]2[C:12]([C:13]([O:15][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:14])=[CH:11][N:10]=[CH:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCCCC1
Reactant: O=C(O)c1cncn1C(c1ccccc1)c1ccccn1
Agent: O=S(=O)(O)O
Product: O=C(OC1CCCCC1)c1cncn1C(c1ccccc1)c1ccccn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 28.8 %

Procedure:
A mixture of 7 parts of 1-[phenyl(2-pyridinyl)methyl]-1H-imidazole-5-carboxylic acid, 5.5 parts of concentrated sulfuric acid and 140 parts of cyclohexanol was stirred for 2 days at 100° C. The reaction mixture was evaporated (at an oil pump) and the residue was taken up in dichloromethane. The organic layer was washed with a sodium hydroxide solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 2.6 parts (28.8%) of cyclohexyl 1-[phenyl(2-pyridinyl)methyl]-1H-imidazole-5-carboxylate; mp. 161.0° C. (compound 1.255).
Reaction SMILES: C(O[C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[N:10][O:11][CH:12]=1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]2[N:38]=[CH:39][C:40](C(Cl)=O)=[C:34]2[N:33]=1>O1CCOCC1.ClCCl>[C:14]1([CH3:19])[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[C:8]([NH:7][C:6]([C:40]2[CH:39]=[N:38][N:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[N:33][C:34]=23)=[O:20])=[CH:12][O:11][N:10]=1
Reactant: Cc1ccccc1-c1nocc1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1nocc1NC(=O)c1cnn2ccc(Cl)nc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of (3-o-tolyl-isoxazol-4-yl)-carbamic acid tert-butyl ester (500 mg, 1.82 mmol, 1.0 equiv), 4M HCl in dioxane (4 mL) in 1,4-dioxane (5 mL) was stirred at ambient temperature for 22 hours and at 40° C. for 1 hour. The mixture was concentrated under vacuum affording a residue which was dissolved in dichloromethane (15 mL) and treated with diisopropylethylamine (523 mg, 4.05 mmol, 2.2 equiv). The mixture was cooled with an ice-bath and a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (1.82 mmol, 1.0 equiv) in dichloromethane (10 mL) was added dropwise. The reaction mixture was warmed to room temperature after the addition. After 65 hours, the solution was sequentially washed with 1M HCl aqueous solution, saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution. The organic was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated (methanol) to give 444 mg (70%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-o-tolyl-isoxazol-4-yl)-amide. LCMS (ESI) m+H=354.2 (mono Cl); 1H NMR (300 MHz, DMSO-d6) δ: 9.47 (s, 1H), 9.36 (d, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 7.53-7.40 (m, 4H), 7.37 (d, 1H), 2.31 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH:18]([CH3:20])[CH3:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:5]1>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:19][CH:18]([CH3:20])[C:2](=[O:1])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:5]1
Reactant: CC(C)C(O)CN1N=C(c2ccc(Cl)cc2)CCC1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(=O)CN1N=C(c2ccc(Cl)cc2)CCC1=O

Procedure:
A solution of 7.0 grams (0.024 mol) of 2-(2-hydroxy-3-methylbutyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone in 2.4 milliliters of acetic acid is cooled with stirring in an icebath, and then over a period of about 5 minutes a solution of 2.2 grams (0.022 mol) of chromium trioxide in 45 milliliters of water is added. The reaction mixture is allowed to stir at room temperature for about 3 hours and then poured onto about 100 milliliters icewater. The mixture is extracted twice with 50 milliliters of methylene chloride and the organic layer is then washed with 30 milliliters of 2 N sodium hydroxide, water, and dried with anhydrous sodium sulfate. After filtration and evaporation to an oil, the product is crystallized from ether to 1.3 grams of 2-(3-methyl-2-oxobutyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone, (m.p. 110°-111° C.)
Reaction SMILES: [Cl-].CC([O-])(C)C.[K+].[CH2:8]([CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:12]1)[CH2:9][CH3:10].C1[CH2:27][O:26][CH2:25]C1>>[CH3:25][O:26][CH:27]=[C:19]1[CH2:20][CH2:21][CH:16]([CH:13]2[CH2:14][CH2:15][CH:11]([CH2:8][CH2:9][CH3:10])[CH2:12]2)[CH2:17][CH2:18]1
Reactant: C1CCOC1
Reactant: CCCC1CCC(C2CCC(=O)CC2)C1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CCCC1CCC(C2CCC(=COC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
THF (100 ml) was added to methoxymethyltriphenylphophnium chloride (29.3 g) in a reaction vessel under an atmosphere of nitrogen, and the solution was cooled to −15° C. t-BuOK (10.5 g) in a THF (50 ml) solution was added, and the stirring was continued for another 1 hour. 4-(3-Propylcyclopentyl)-cyclohexanone (15.0 g) in a THF (50 ml) solution was added dropwise, and the stirring was continued for another 2 hours. The reaction mixture was warmed to room temperature and was extracted with toluene after the addition of water (200 ml). The resulting organic layer was washed with water and dried over anhydrous sulfate, and the toluene was concentrated to a volume of about 100 ml under reduced pressure. The concentrate was poured into n-hexane (500 ml) and solids deposited were filtered off. The solvent of the resulting solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/9 by volume) to give 1-methoxymethylene-4-(3-propylcyclopentyl)cyclohexane (17.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:23])[C:10]([CH3:22])([CH3:21])[CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[F:20])=[CH:4][CH:3]=1.C(O)(=O)C.C(N(CC)CC)C.Br[CH:36]([CH:39]=O)[CH:37]=[O:38]>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:36]([CH:37]=[O:38])=[CH:39][N:23]=[C:9]2[C:10]([CH3:21])([CH3:22])[CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[F:20])=[CH:4][CH:3]=1
Reactant: O=CC(Br)C=O
Reactant: CC(C)(Cc1c(F)ccc(F)c1F)C(=N)Nc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(Cc1c(F)ccc(F)c1F)c1ncc(C=O)n1-c1ccc(F)cc1

Procedure:
A solution of N-(4-fluorophenyl)-2,2-dimethyl-3-(2,3,6-trifluorophenyl) propanimidamide (35) (72.8 mg, 0.22 mmol), acetic acid (14 μL, 0.24 mmol), triethylamine (33 μL, 0.24 mmol), and bromomalonaldehyde (33.9 mg, 0.22 mmol) in isopropyl alcohol (1 mL) was refluxed for 4 h. The reaction was concentrated in vacuo, dichloromethane was added and washed with water. The aqueous phase was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to afford 1-(4-fluorophenyl)-2-(2-methyl-1-(2,3,6-trifluorophenyl)propan-2-yl)-1H-imidazole-5-carbaldehyde (36).
Reaction SMILES: [CH2:1]1[O:14][C:13]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)[O:2]1.[H-].[Na+].[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][Cl:22].Cl.C(N1CCC2C=C3OCOC3=CC=2CC1)C=C.Cl>CN(C)C=O.O>[ClH:22].[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]3[O:2][CH2:1][O:14][C:13]3=[CH:12][C:6]=2[CH2:7][CH2:8]1
Reactant: CN(C)CCCCl
Reactant: c1c2c(cc3c1OCO3)CCNCC2
Agent: C=CCN1CCc2cc3c(cc2CC1)OCO3
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCc2cc3c(cc2CC1)OCO3

Procedure:
The free base was prepared from 1.9 g of 2,3,4,5-tetrahydro7,8-methylenedioxy-1H-3-benzazepine (0.01 moles), 0.49 g of sodium hydride (0.011 moles), and 2.42 g of 3-dimethylaminopropyl chloride in 15 ml of dimethylformamide in the same manner as described for 3-allyl-2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine hydrochloride. After treating the reaction mixture with water and extracting with ether (6 × 25 ml) a yellow oil was obtained. This oil was converted to the hydrochloride and the salt recrystallized from EtOH-EtOAc twice to yield the abovenamed product as a white solid, m.p. 273°-275° (dec).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1C=O.C(O[CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:16]([O:15][CH:11]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1nccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)c1nccs1
Reaction time: 16 h

Procedure:
A mixture of 2-thiazole carboxaldehyde (25 g, 221 mmol), triethylorthoformate (46 mls, 41 g, 276 mmol) and para-toluenesulphonic acid (1.52 g, 9 mmol) in ethanol (200 ml) was sured for 16 hours under a nitrogen atmosphere at ambient temperature. A further amount of para-toluenesulphonic acid (2 g, 11 mmol) was added and the reaction stirred for another 16 hours. The mixture was treated with sodium bicarbonate to pH 9, stirred for a further 5 minutes and then filtered and the filtrate evaporated to dryness to give 2-(1,1-diethoxymethyl)thiazole as a clear oil, which was used without flirher purification (41 g, 99%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH3:14])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:15]([Cu])#[N:16]>CN(C=O)C.N1C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:5]([CH3:14])[CH:4]=[N:3][C:2]=2[C:15]#[N:16])=[CH:8][CH:9]=1
Reactant: Cn1cnc(Br)c1-c1ccc(Cl)cc1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1cnc(C#N)c1-c1ccc(Cl)cc1
Temperature: 200 °C

Procedure:
To 4-bromo-5-(4-chlorophenyl)-1-methyl-1H-imidazole (1.3 g, 4.79 mmol) in DMF (8.4 mL) and pyridine (1.6 mL) was added CuCN (1.3 g, 14.4 mmol). The reaction was heated in a microwave reactor at 200° C. for 35 min. After cooling to ambient temperature, the reaction was quenched by addition of a 3:1 solution of NH4OH/saturated aqueous NH4Cl (60 mL). The reaction was extracted with EtOAc, organics separated, washed with saturated aqueous NaHCO3, and dried with saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide desired product and recovered starting material. The recovered starting material was resubjected to the reaction conditions and purified as above to provide additional desired product. MS (m/z) 218.3 [M+H]+.