Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:7]1[N:11]2[C:12]3[C:26]4[CH:27]=[N:28][NH:29][C:25]=4[N:24]=[CH:23][C:13]=3[C:14](=[O:22])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[N:9][CH2:8]1)C1OC=CC=1.COCCOCCOC.[Se](=O)=O>>[C:16]1([N:15]2[C:14](=[O:22])[C:13]3[CH:23]=[N:24][C:25]4[NH:29][N:28]=[CH:27][C:26]=4[C:12]=3[N:11]3[N:7]=[CH:8][N:9]=[C:10]23)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1c2cnc3[nH]ncc3c2N2C(=NCN2Cc2ccco2)N1c1ccccc1
Agent: O=[Se]=O
Solvent: COCCOCCOC
Product: O=c1c2cnc3[nH]ncc3c2n2ncnc2n1-c1ccccc1
Reaction time: 2 h

Procedure:
0.01 mol. of 1-furfuryl-4-phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is heated in 50 ml. of diethyleneglycol dimethylether containing 0.01 mol. of selenium dioxide at reflux temperature with stirring for two hours. The mixture is filtered hot and evaporated to dryness. 4-Phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidin-5(8H)-one remains.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>>[C:1]([C:5]1[C:6]([NH:14][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)Cc2ccc(F)cc2)nn2cccnc12

Procedure:
The product from Example 105B and 4-fluorophenylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 3.63 (s, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 7.13-7.18 (m, 2H), 7.31-7.41 (m, 2H), 8.48 (dd, J=4.1, 1.7 Hz, 1H), 8.91 (dd, J=7.1, 1.7 Hz, 1H), 9.94 (s, 1H); MS (DCI) m/z 327 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH3:8])([CH2:5][OH:6])[CH2:3][OH:4].[C:9](=O)(OCC)[O:10]CC>C[O-].[Na+].CCO>[CH2:7]([C:2]1([CH2:5][OH:6])[CH2:3][O:4][C:9](=[O:10])[NH:1]1)[CH3:8]
Reactant: CCOC(=O)OCC
Reactant: CCC(N)(CO)CO
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(CO)COC(=O)N1
Yield: 66.5 %

Procedure:
Sodium methoxide (2.2 g, Aldrich) was added to a solution of 2-amino-2-ethyl-1,3-propanediol(100.0 g, Aldrich) and diethyl carbonate (169.0 g, Aldrich) This solution was refluxed in a Dean Stark apparatus until no more EtOH was collected. The reaction mixture was cooled, added acetone(200 ml) and allowed to stand overnite at room temperature. The resulting suspension was filtered to give 81.0 g of the desired product as a beige solid. 1H NMR consistent with the proposed structure.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]([F:43])([F:42])[C:31]1[CH:41]=[CH:40][C:34](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:33][CH:32]=1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:37](=[O:38])/[CH:36]=[CH:35]/[C:34]4[CH:33]=[CH:32][C:31]([C:30]([F:42])([F:43])[F:29])=[CH:41][CH:40]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-4-(trifluoromethyl)-cinnamic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C31H35F3N4O2: 553 (M+H). Found: 553
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)(=[O:25])=[O:26])=[CH:20][C:16]=2[C:17]([NH:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.05 ml, 0.59 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 2-[(phenylmethyl)oxy]-5-(1-piperidinylsulfonyl)benzoic acid (may be prepared as described in Description 69; 220 mg, 0.59 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h, and then concentrated under reduced pressure to give crude acyl chloride. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (55.1 mg, 0.59 mmol) and diisopropylethylamine (0.10 ml, 0.59 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times, saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give crude product as a orange oil. The product was crystallized from methanol to yield the title compound as a white solid. 125 mg.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][N:19]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:17][C:18]1[N:19]=[CH:20][C:21]([CH2:24][N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C:4]2=[O:3])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)nc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred ice-cooled suspension of sodium hydride, (60% dispersion in mineral oil, 0.83 g, 21 mmol) in DMF (15 mL) was added a suspension of tert-butyl 3-oxopiperazine-1-carboxylate (2.5 g, 12 mmol) in DMF (45 mL) through a syringe. The ice-H2O bath was removed and the resulting mixture, which was a suspension, was stirred at ambient temperature for 30 min. Complete dissolution was observed. 2-chloro-5-(chloromethyl)pyridine (2.0 g, 12 mmol) was added in one portion as a solid. The resulting mixture was stirred at ambient temperature for 18 h then poured into ice and saturated NaHCO3 aqueous solution. It was extracted with ethyl acetate (2×). The combined organics were washed with saturated NaHCO3 aqueous solution (3×), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM) to give compound 358 (3.65 g, 91% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.31 (1 H, d, J=2.2 Hz), 7.65 (1 H, dd, J=8.3, 2.4 Hz), 7.33 (1 H, d, J=8.1 Hz), 4.59 (2 H, s), 4.15 (2 H, s), 3.62 (2 H, t, J=5.4 Hz), 3.29 (2 H, t, J=5.1 Hz), 1.46 (9 H, s). LCMS-ESI (POS), M/Z, M+1: Found 326.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH2:20][CH2:21][OH:22]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:19]([CH3:18])[CH2:20][CH2:21][OH:22]
Reactant: CNCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(CCO)c1ccc([N+](=O)[O-])cc1F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of 554 μL (5.0 mmol) of 3,4-difluoronitrobenzene in 10 mL of dimethyl sulfoxide were added 1.38 mg (10.0 mmol) of potassium carbonate and 803 μL (10.0 mmol) of 2-methylaminoethanol, and the mixture was stirred for 1.5 hours at 100° C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate, then, the extract was washed with water and saturated saline solution. After dried over with anhydrous sodium sulfate, the solvent was removed under reduced pressure ant the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 1.06 g (99%) of the title compound.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:15][CH2:14]1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10]([NH2:9])=[S:11])[CH2:18][CH2:17]2)=[CH:22]1
Reactant: O=C(NC(=S)NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=S)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 96.7 %

Procedure:
1-Benzoyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]-thiourea (2.21g) was refluxed in water (20 ml) containing sodium hydroxide (1.0 g) for 5 min. The mixture was cooled and filtered to afford the title compound (1.59g). Crystallisation from EtOH-HCl/ether afforded the hydrochloride (1.467g), m.p. 228°-9°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26](OC)=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=3[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21.[BH4-].[Li+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:26]=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=3[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(OC)nc(C)nc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc(C)nc(OC)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 0 °C
Reaction time: 15 h
Yield: 75.5 %

Procedure:
To a stirred solution of methyl 9-chloro-1-(4,6-dimethoxy-2-methylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (627 mg, 1.50 mmol) in tetrahydrofuran (15 mL) was added lithium borohydride (131 mg, 6.00 mmol) at room temperature. After being stirred for 15 h at 0° C., the reaction mixture was quenched with aqueous ammonium chloride, extracted with ethyl acetate, and concentrated in vacuo. The resulting solid was washed with ethyl acetate and dissolved in dimethyl sulfoxide (15 mL). To the solution was added Dess-Martin reagent (1.27 g, 3.00 mmol) at room temperature, and the mixture was stirred for 15 h. The reaction mixture was diluted with ethyl acetate, quenched with aqueous sodium hydrogen carbonate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-80% ethyl acetate/hexane gradient mixture to give the title compound as a pale yellow solid (439 mg, 75%).
Reaction SMILES: [CH3:1][NH:2]C(=O)N.C1([O:12][C:13](=O)[NH:14][CH2:15][C:16]#[C:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][N:22]=[C:21]3[NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=3)=[C:31]([Cl:43])[CH:30]=2)C=CC=CC=1.CN>CS(C)=O>[Cl:43][C:31]1[CH:30]=[C:29]([NH:28][C:21]2[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([C:17]#[C:16][CH2:15][NH:14][C:13]([NH:2][CH3:1])=[O:12])[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:34]=[CH:33][C:32]=1[O:35][C:36]1[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(C#CCNC(=O)Oc5ccccc5)cc34)cc2Cl)cn1
Reactant: CNC(N)=O
Agent: CN
Solvent: CS(C)=O
Product: CNC(=O)NCC#Cc1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(Cl)c3)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
1-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-3-methyl-urea: A mixture of (3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy) phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid phenyl ester (0.1 g, 0.18 mmol) prepared by Method B, methyl amine (2.0M methanol solution, 1 mL, 2 mmol) and DMSO (0.5 mL) was stirred at 80° C. overnight. The solvents were removed under vacuum (GeneVac HT-8) and the residue was re-dissolved in MeOH (˜1 mL). HCl gas was bubbled through the solution and EtOAc resulting in precipitation of the desired product. The title compound (80 mg, 90% yield) was obtained by filtration as a yellow solid. 1HNMR (400 MHz, CD3OD) δ 2.72 (3H,s), 2.76 (3H, s), 4.19 (2H, s), 7.49 (1H, d, J=9 Hz), 7.84 (1H, d, J=2 Hz), 7.86 (1H, d, J=2 Hz), 7.92 (1H, d, J=9 Hz), 8.12 (2H, m, J=2 Hz), 8.16 (1H, d, J=2.4 Hz), 8.60 (1H, d, J=3.2 Hz), 8.74 (1H, d, J=1.2 Hz), 8.87 (1H, s). LRMS (M+): 473.0, 475.0, 476.0.
Reaction SMILES: [N:1]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[N+]=[N-].C(N(CC)CC)C.Br.[Br:19][CH2:20][CH2:21]N>C(Cl)Cl>[C:4]([NH:1][CH2:21][CH2:20][Br:19])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCBr
Reaction time: 3 h

Procedure:
A mixture of t-butyl azidoformate (15.81 g) and triethylamine (30 ml) was added dropwise to a stirred suspension of 2-bromoethylamine hydrobromide (20.5 g.), in methylene chloride (100 ml.). The mixture was stirred for 3 hr., then filtered. The filtrate was concentrated to a small volume, and the residue was distributed between ether and water. The ether layer was dried, then distilled under reduced pressure, collecting the fraction b.p. 92°-94°/0.9 mm as N-carbo-t-butoxy-2-bromoethylamine (1.756 g.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:28])=[C:4]([CH:10]2[N:15]([CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:29]C1C=CC(S(O)(=O)=O)=CC=1.C(OCC)(OCC)OCC>CCOC(C)=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:29][O:28][C:3]=2[C:4]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:14](=[O:27])[CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(N)c(O)c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: COc1ccc2ncoc2c1C1CCCC(=O)N1Cc1ccc2ccccc2n1
Temperature: 100 °C

Procedure:
A mixture of 6-(3-amino-2-hydroxy-6-methoxyphenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one (100 mg; 0.26 mmol; synthesis described in example 279), commercially available p-TsOH (2 mg; 0.01 mmol), and commercially available triethyl orthoformate (264 mg; 1.69 mmol) was refluxed (100° C.) for 1 h. After cooling to rt, AcOEt was added, and the obtained mixture was filtered over a pad of celite. The filtrate was then washed with water and brine, and the mixed aq. layers were further extracted with AcOEt. The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by FC (DCM/MeOH=20/1) afforded the target compound. LC-MS (conditions A): tR=0.53 min.; [M+H]+: 388.05 g/mol.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>ClCCl.C(N(CC)CC)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:34])=[O:33])[CH:27]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1cccnc1
Reaction time: 5 h
Yield: 68 %

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (370 mg) was dissolved in 20 ml of dichloromethane and 1 ml of triethylamine. Pyridine-3-sulfonyl chloride (195 mg) was added and stirred in ice-bath for 5 hr. Dichloromethane layer was washed with an aqueous solution composed of 0.1M NaCl and 0.1M sodium bicarbonate. Dichloromethane layer was dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure. Residual material was precipitated by dichloromethane-ethyl ether-heptane to provide 348 mg of 1-(pyridine-3-sulfonyl)-2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1([CH3:22])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>>[CH3:15][C:16]1([CH3:22])[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:17]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: CC1(C)CCCNC1
Product: CC1(C)CCCN(c2nnc(N)nc2-c2ccccc2)C1
Yield: 9.6 %

Procedure:
6-(3,3-Dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3,3-dimethylpiperidine (0.27 g, 2.39 mmol) according to the general procedure of Example 2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:49](=O)[CH2:50][CH2:51][CH3:52])[C:44](OCC)=[O:45])=[CH:38][C:37]=1[N+:54]([O-:56])=[O:55])#[N:29].C(OCC)(=O)C>CCN(C1C=CC=CC=1)CC.O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:44](=[O:45])[C:43]([CH2:42][C:39]4[CH:40]=[CH:41][C:36]([C:31]5[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:37]([N+:54]([O-:56])=[O:55])[CH:38]=4)=[C:49]([CH2:50][CH2:51][CH3:52])[N:16]4[N:15]=[CH:14][CH:13]=[C:12]34)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c([N+](=O)[O-])c1)C(=O)OCC
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c([N+](=O)[O-])c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Yield: 86 %

Procedure:
A solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (0.45 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.060 mL) and ethyl 2-[(2′-cyano-2-nitrobiphenyl-4-yl)methyl]-3-oxohexanoate (1.6 g) in diethylaniline (2 mL) was stirred at 180° C. for 2 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.96 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:24][C:25]#[C:26][CH3:27]>>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:24][C:25]#[C:26][CH3:27])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CC#CCBr
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccccc1OC
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccccc2OC)cc1
Yield: 87 %

Procedure:
Ethyl(2-methoxyphenyl){[4-(2-butynyloxy)phenyl]sulfanyl}acetate was prepared according to the general method as outlined in example 1 (step 2), starting from ethyl (2-methoxyphenyl)[(4-hydroxyphenyl)sulfanyl]acetate (3.2 g, 10 mmol) and 1-bromo-2-butyne (1.5 g, 11.2 mmol); 3.2 g clear oil. Yield 87%; MS(EI): 371 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[F:15])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(Nc1cc(Br)ccc1F)C(F)(F)F
Product: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Yield: 78.4 %

Procedure:
N-(5-Bromo-2-fluorophenyl)-2,2,2-trifluoroacetamide (8.04 g, 28 mmol) and (trimethylsilyl)acetylene (6 mL, 42 mmol) were coupled according to the procedure of Example 56, Step B to give the desired product (6.66 g, 78%). 1H NMR (400 MHz, d6-DMSO) δ 11.32 (s, 1H), 7.62-7.60 (m, 1H), 7.47-7.44 (m, 1H), 7.39-7.33 (m, 1H), 0.21 (s, 9H) ppm.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CO.O.[Fe]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[CH:15][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(N)cc1
Temperature: 50 °C
Yield: 99.8 %

Procedure:
To a solution of N-methyl-4-nitroaniline (5.0 g, 32.9 mmol) in THF (50 mL) were added di-tert-butyl dicarbonate (10.76 g, 49.4 mmol) and DMAP (201 mg, 1.6 mmol). The reaction mixture was refluxed under N2 for 2 h before cooled to rt. After removal of the solvent, the residue was dissolved with EtOAc (200 mL). The resulting solution was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to give tert-butyl methyl(4-nitrophenyl)carbamate (8.3 g, 100%) as a brown oil. To a solution of tert-butyl methyl(4-nitrophenyl)carbamate (8.3 g, 32.9 mmol) in THF/MeOH/H2O (150 mL/40 mL/80 mL) was added Fe powder (9.4 g, 168 mmol) and NH4C1 (18 g, 337 mmol). The reaction mixture was heated at 50° C. for 4 h under N2. After cooling to rt, the reaction mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc (100 mL×3), washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 4-aminophenyl(methyl)carbamate (36) (7.3 g, yield 100%) as a yellow solid. LC-MS (ESI): m/z (M+1) 223.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>O1CCOCC1>[C:16]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Temperature: 80 °C
Reaction time: 60 h

Procedure:
To a solution of the product from Step 1 (5.34 g) in dioxane (25 ml) was added acetic anhydride (6 ml) and pyridine (4 ml). After 60 hours of stirring at 80° C., the solution was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The organic layer was washed with 2M sodium carbonate, 10% aqueous HCl, water and brine, dried over sodium sulfate and evaporated. The product was purified by flash chromatography (ISCO, 5%-20% ethyl acetate in hexanes) to provide a beige solid (5.27 g). LRMS (ES+) m/z 262.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[CH2:24][N:29]2[C@H:28]([CH3:27])[C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:7]=1)[CH3:2]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)cc(C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.