Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.S(=O)(O)[O-].[Na+]>CO>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:10][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=3[N:9]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc3ccc(OC)cc3[nH]2)cc1
Yield: 66.2 %

Procedure:
4-Methoxybenzene-1,2-diamine (1.96 g, 14.2 mmol), 4-formylbenzoic acid methyl ester (2.33 g, 14.2 mmol) and sodium bisulphite (1.55 g, 14.9 mmol) were refluxed in methanol (50 mL) for 3 h, then evaporated to dryness. The solid residue was partitioned between dichloromethane and water. The organic layer was dried, evaporated and purified by column chromatography, eluting with. The title compound (2.65 g, 9.40 mmol, 66%) was obtained as a dark solid.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:11][C:8]1[CH:7]=[N:6][C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:21]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=3)=[C:17]([F:16])[CH:22]=2)=[N:10][CH:9]=1
Reactant: Nc1cnc(Oc2ccccc2Br)nc1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1cnc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidin-5-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H15FN6O, 374.13; m/z found, 374.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=1.5, 2H), 7.95-7.90 (m, 2H), 7.57-7.50 (m, 2H), 7.44-7.39 (m, 1H), 7.38-7.37 (m, 1H), 7.36-7.34 (m, 1H), 7.33-7.28 (m, 1H), 7.11 (dd, J=8.1, 1.2, 1H), 6.86 (s, 2H), 5.19 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:42]([CH:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]2)=[O:43])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (74) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1 -tert-Butoxycarbonyl-piperidine4-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (30%→50% ethyl acetate in hexanes) affording the desired product (75) as a solid. ESMS:MH+ 590.6
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:21](=[O:22])[C:20]4[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=4)[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.78 g (40 mmol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 88 ml of methylene chloride and 7.70 g (44 mmol) of 4-chlorobenzoyl chloride in 60 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour the mixture was extracted with water, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 2:1) and crystallization (chloroform-hexane) gave 8-chloro-4 (p-chlorobenzoyl)-1,2,3,4,5,6 -hexahydrobenzo[f]quinoline as white crystals of melting point 189°-191°.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:17]1[CH2:21][CH:20]=[CH:19][CH:18]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[C@@H:19]12[CH2:20][C@H:21]([CH:17]=[CH:18]1)[C@H:3]1[C@@H:2]2[C:1](=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1C=CCCCCCCCCCCCC1
Reactant: C1=CCC=C1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: O=C1/C=C/CCCCCCCCCCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: O=C1CCCCCCCCCCCC[C@@H]2[C@H]1[C@H]1C=C[C@H]2C1
Yield: 88 %

Procedure:
Prepared according to general procedure A from trans-2-cyclopentadecen-1-one (100 mg, 0.45 mmol), cyclopentadiene (56 μL, 0.67 mmol), 70% aqueous perchloric acid (7.8 μL, 0.09 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (24.3 mg, 0.09 mmol) in water (150 μL) for 72 hours at 0° C. Purification by flash chromatography (9:1 ethyl acetate:hexanes) provided the title compound as a clear, colorless crystalline solid in 88% yield (114 mg, 0.50 mmol); 5:1 endo:exo, endo 93% ee. IR (film) 3052, 2922, 2854, 1698, 1456, 1368, 1331, 1225, 1126, 1084, 1016, 905.5, 884.9, 714.4 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.21 (dd, J=5.4, 2.7 Hz, 1H, CH═CH), 5.86 (dd, J=5.4, 2.7 Hz, 1H, CH═CH), 3.09 (m, 1H, CHCH═CH), 2.61 (m, 2H, CHCO and one of CH2CO), 2.52 (m, 1H, CHCH═CH), 2.41 (m, 1H, one of CH2CO), 2.27 (m, 1H, CHCHCO), 1.81-1.24 (br m, 22H, (CH2)11); 13C NMR (75 MHz, CDCl3) δ 211.6, 138.5, 132.6, 59.6, 48.4, 47.2, 46.7, 41.5, 41.3, 36.3, 28.0, 27.9, 27.7, 27.2, 26.8, 26.8, 26, 26.7 26.0, 23.6. [α]D=+22.2 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (200° C., 23 psi); (1R, 2R, 16S, 17S) endo isomer tr=20.1 min, and (1S, 2S, 16R, 17R) endo isomer tr=19.6 min, exo isomers tr=19.0, 18.6 min. The trans relative stereochemistry of C-16 and C-17 was confirmed by the presence of an NOE between the C-16 methine proton and the two C-19 protons.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>C1COCC1.O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:4]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCc1cccnc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a suspension of 4.4 g of sodium hydride (60% oil dispersion; 110 mmol) in 300 mL of THF were added dropwise 10.91 g of 3-pyridinemethanol (100 mmol) in 20 mL of THF at room temperature, and the mixture was stirred at room temperature for 2 hours. The resulting white suspension was ice-cooled, and 19.51 g of tert-butyl bromoacetate (100 mmol) in 20 mL of THF was added dropwise, maintaining the inner temperature within 10 to 12° C. The suspension was warmed to room temperature with stirring for 3 hours, and then left overnight. After adding water and saturated sodium bicarbonate aq., the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (gradient elution with n-hexane:ethyl acetate=1:1 to ethyl acetate) to give 7.56 g of tert-butyl (pyridin-3-yl)methoxyacetate (33.8%) as a light brown oil.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=O)[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:23]([CH2:25][C:26]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH3:24].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([N:23]([CH2:25][C:26]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[O:27])[CH3:24])=[O:12])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Reactant: CNCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
254 mg of Z-Sta-OH (see stage 1.12), 297 mg of H-Sar-His-Lys(Boc)-OMe, 97 mg of HOBt×H2O and 196 mg of DCCI are dissolved, in this sequence, in 3 ml of DMF and the whole is left to stand for 20 hours at room temperature. The DCH which has crystallised out is filtered off, the filtrate is concentrated to dryness, heated for 1 hour at 60° in 7 ml of methanol/glacial acetic acid/H2O (94:3:3), and this solution is again concentrated to dryness. The oily residue is purified by chromatography over 75 g of silica gel (Merck No. 60, 230-400 mesh) by elution with CHCl3 /MeOH (9:1). The pure fractions are dissolved in ethyl acetate, washed with NaHCO3 solution and with H2O and, by concentration of the organic phase, Z-Sta-Sar-His-Lys(Boc)-OMe is obtained in amorphous form (honey); Rf (F)=0.15; Rf (I)=0.5.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([F:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.O.[CH3:20]O>>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([F:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: COc1c(Br)cc(C(=O)O)c(O)c1F
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Br)c(OC)c(F)c1O
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoic acid (0.70 g) in methanol (15.0 mL) was added dropwise thionyl chloride (0.39 mL) under ice-cooling. The reaction solution was stirred at 70° C. for 15 hr under argon atmosphere, and then overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.52 g).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:15])[C:7](=[O:14])[CH2:8][CH2:9][N:10]2[CH3:13])=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:22])=[CH:19][C:18]=1[O:33][CH3:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH3:13][N:10]1[CH2:9][CH2:8][C:7](=[O:14])[N:6]([CH3:15])[C:5]2[C:11]1=[N:12][C:2]([NH:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[O:22])=[CH:19][C:18]=1[O:33][CH3:34])=[N:3][CH:4]=2
Reactant: CN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C)CCC(=O)N2C
Temperature: 25 °C
Yield: 48.4 %

Procedure:
10-Chloro-2,6-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 9; 185 mg, 0.82 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (215 mg, 0.82 mmol) and p-toluenesulphonic acid (389 mg, 2.05 mmol) in (R/S)-4-methyl-2-pentanol (6 mL) were heated at 115° C. for 5 h. The reaction mixture was cooled to ambient temperature then passed through a SCX-2 cartridge and washed with MeOH (40 mL). The crude product was eluted off the SCX-2 cartridge with NH3 (40 mL, 7M in MeOH). Purification by preparative HPLC (Gemini RP C18 30×100 mm, gradient mobile phase: 10-80% MeCN/water+0.5% NH3) afforded the title compound (180 mg, 48%) as a foam.
Reaction SMILES: [Br:1][C:2]([F:12])([F:11])[S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4].[N:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1.O>[Br:1][C:2]([F:11])([F:12])[S:3]([C:6]1[N:10]=[CH:9][N:8]([C:18]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:19])[N:7]=1)(=[O:4])=[O:5]
Reactant: O=S(=O)(c1nc[nH]n1)C(F)(F)Br
Reactant: O=C(Cl)N1CCCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(N1CCCC1)n1cnc(S(=O)(=O)C(F)(F)Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a solution of 0.12 g (0.45 mmol) 3-(bromodifluoromethylsulfonyl)-1,2,4-triazole, prepared as above, in 0.5 ml dry pyridine was added 0.07 g (0.54 mmol) pyrrolidine-1-carbonyl chloride and the mixture was agitated for 16 h at room temperature. The reaction mixture was then diluted with water and extracted with ether. The resulting organic layer was washed successively with dilute hydrochloric acid, water and saturated sodium bicarbonate solution, dried over MgSO4 and evaporated to give 0.1 g (65% yield) of the desired 3-(bromodifluoromethylsulfonyl)-1-(pyrrolidinocarbonyl)-1,2,4-triazole as a pale yellow oil: 1H NMR (CDCl3) δ(ppm) 9.1 (1H), 4.0 (2H), 3.7 (2H), 2.1 (4H).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH:28][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:23][CH:22]=1
Reactant: COc1ccc(OCCN)cc1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(OCCNc2nc(Nc3cc(C)[nH]n3)cc(C)c2C#N)cc1
Temperature: 100 °C
Reaction time: 27 h
Yield: 19.4 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(4-methoxyphenoxy)ethylamine hydrochloride (489 mg) and sodium hydrogencarbonate (1.37 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(4-methoxyphenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (98 mg).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([CH2:19][O:18][CH2:17][CH2:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:7]=1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1

Procedure:
Reaction of 4-trifluoromethyl-1H-imidazole (301 mg, 2.21 mmol), 95% NaH (61 mg, 2.4 mmol), and SEMCl (406 mg, 2.44 mmol) gave the title compound as a brown oil that was used without further purification. 1H NMR (CDCl3) □ 0.00 (s, 9H), 0.93 (m, 2H), 3.51 (m, 2H), 5.30 (s, 2H), 7.39 (s, 1H), 7.64 (s, 1H).
Reaction SMILES: [O:1]([C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH:19]=[C:11]1[C:10](=[O:13])[CH2:9][N:8]([C:6]([O:1][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:7])[CH2:12]1)[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C

Procedure:
A solution of 1-(tert-butoxylcarbonyl)-3-pyrrolidone (4.10 g) and N,N-dimethylformamide dimethyl acetal (30.0 mL) was heated to 140° C. for 1 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in a minimum amount of dichloromethane and triturated with hexane to yield a yellow precipitate. LC-MS=241.1 (M+1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][N:9]1[C:8](=[O:26])[C:7]([C:6]2[CH:5]=[CH:4][S:3][C:2]=2[C:32]2[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]1=[O:24]
Reactant: Cc1c(-c2ccsc2Br)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccsc2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 91.9 %

Procedure:
To a solution of 5-(2-bromothiophen-3-yl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 200) (17.0 mg), 4-cyanophenylboronic acid (11.2 mg) and sodium carbonate (20.2 mg) in tetrahydrofuran (1.0 ml)/water (0.2 ml) was added tetrakis(triphenylphosphine)palladium (4.4 mg) and the resulting mixture was stirred with heating under reflux for twelve hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[3-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]thiophen-2-yl]benzonitrile (16.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+]([O-])=O)[C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F-:15].[K+]>C1S(=O)(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:15])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [F-]
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1cc(F)c(F)cc1Cl
Temperature: 150 °C

Procedure:
The combined benzoic acids made in each of Examples 3, 11 and 12 (consisting of compounds 5 and 6 in a ratio of about 2:1) were converted to the corresponding acid chlorides as in Example 4. The acid chlorides (2 g, 8.4 mmol) were dissolved in 4 ml of tetramethylenesulfone and treated with spray-dried KF (2.0 g, 34.5 mmol). The mixture was heated at 150° C. under nitrogen for 3 hours and the product distilled at 70°-75° C./15 mm. The acid fluoride collected was hydrolyzed with water and the product was dried in vacuum to give pure compound 8 as the only product (0.4 g, 24%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[CH2:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[CH2:4][C:3]=1[C:14]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: Nc1ccccc1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)C1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1=C(O)c2ccccc2S(=O)(=O)C1

Procedure:
Preparation by Aminolysis of the β-Ketoester. -- A mixture of 11.7 g. (0.05 mole) of methyl 4-hydroxy-2H-1-benzothiopyran-3-carboxylate 1,1-dioxide, 7.0 g. (0.075 mole) of aniline, and 250 ml. of xylene was refluxed for 16 hr. in a Soxhlet apparatus, the thimble of which contained 20 g. of Linde type 4A molecular sieve. The mixture was cooled and the resulting precipitate was collected to give 12.8 g. (81%) of product, m.p. 204°-208° dec. Recrystallization from ethyl acetate gave 11.4 g. material, m.p. 205°-208° dec.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=O)=[C:4]([O:12][CH2:13][C:14]#[CH:15])[CH:3]=1.[O-]S([O-])(=O)=O.[Mg+2].[CH3:22][N:23]([CH3:25])[NH2:24]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[N:24]/[N:23]([CH3:25])[CH3:22])=[C:4]([O:12][CH2:13][C:14]#[CH:15])[CH:3]=1
Reactant: CN(C)N
Reactant: C#CCOc1cc(Br)ccc1/C=C/C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C#CCOc1cc(Br)ccc1/C=C/C=N/N(C)C
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of (E)-3-(4-bromo-2-(prop-2-ynyloxy)phenyl)acrylaldehyde (2.85 g, 10.8 mmol) in dichloromethane (200 mL) containing anhydrous MgSO4 (16 g) was cooled in an ice bath with stirring. To the ice-cold solution was added 1,1-dimethylhydrazine (2.45 mL, 32.4 mmol) dropwise and the reaction mixture was allowed to warm up to ambient temperature and was stirred for 18 h. The volatiles were concentrated under reduced pressure and the residue was coevaporated sequentially with dichloromethane (50 mL), dichloroethane (50 mL) and heptane (50 mL). (E)-2-((E)-3-(4-bromo-2-(prop-2-ynyloxy)phenyl)allylidene)-1,1-dimethylhydrazine (2.7 g, 8.79 mmol, 90% yield, 90% purity) was obtained as a yellow powder. 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J=7.9 Hz, 1H), 7.20-7.10 (m, 3H), 7.00-6.86 (m, 2H), 4.75 (d, J=2.3 Hz, 2H), 2.95 (s, 6H), 2.58 (t, J=2.3 Hz, 1H); LCMS (Method B) (ESI) m/e 307.0, 309.0 Br pattern [(M+H)+, calcd for C14H15BrN2O 307.0].