Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:7][CH2:6]1)(O)=[O:2].[NH:35]1[C:39]([NH2:40])=[N:38][N:37]=[N:36]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CN(C=O)C>[NH:35]1[C:39]([NH:40][C:1]([CH2:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[F:34])=[O:26])[CH:20]=4)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)=[O:2])=[N:38][N:37]=[N:36]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1)Nc1nnn[nH]1

Procedure:
A DMF (4 mL) solution of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester (188 mg) obtained in Example 2, 1H-tetrazol-5-ylamine (54 mg), BOP reagent (212 mg), and diisopropylethylamine (0.10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with 1 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was concentrated and vigorously stirred in water/isopropyl ether. The obtained solid was heated to reflux in methanol and collected by filtration. The title compound (99 mg, 46%) was obtained as a pale yellow solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)=O>[CH:5]([NH:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1CCc1ccccn1
Solvent: O=CO
Product: O=CNc1ccccc1CCc1ccccn1
Temperature: 25 °C
Yield: 83 %

Procedure:
An aceticformic anhydride mixture is prepared by mixing acetic anhydride (140 ml.) and formic acid (70 ml.). To this mixture, 2-(o-aminophenethyl)pyridine (59 g., 0.3 mole) is added in one portion with vigorous stirring at 25°C. After 15 minutes the solution is diluted with 450 ml. of water and concentrated in vacuo. The resulting residue is taken up in 1 liter of water and made basic with 50% sodium hydroxide. The basified solution is extracted with chloroform, the chloroform extract washed with water, dried over magnesium sulfate and the chloroform solvent evaporated. Crystallization of the residue from isopropyl acetate provides 57 g. (83% yield) of 2-(o-formamidophenethyl)pyridine melting at 78°-81°C. (uncorrected). An analytical sample (from isopropyl acetate) has a melting point of 83°-83.5°C. (corr.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:14][CH2:15][CH3:16].COC(O)C1C=C([N+]([O-])=O)C=CC=1OC>>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:14][CH2:15][CH3:16])=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCCI
Agent: COc1ccc([N+](=O)[O-])cc1C(O)OC
Product: CCCOc1ccc([N+](=O)[O-])cc1C=O
Yield: 72 %

Procedure:
This compound was prepared by the reaction of 2-hydroxy-5-nitrobenzaldehyde and 1-iodopropane using a similar procedure as described in the preparation of 2-methoxy-5-nitrobenzaldehyde methyl hemiacetal. Yield was 72%: MP (51-52° C.); 1H NMR (500 MHz, CDCl3) δ 10.46 (s, 1H), 8.68 (d, 1H, J=2.9 Hz), 8.39 (dd, 1H, J=2.7 and 9.1 Hz), 7.08 (d, 1H, J=9.1 Hz), 4.16 (t, 2H, J=6.2), 1.93 (m, 2H), 1.98 (t, 3H, J=7.37).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]([CH3:13])=[N+:9]([O-:22])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncccc1C1CCCCC1
Solvent: ClCCl
Product: Cc1c(C2CCCCC2)ccc[n+]1[O-]
Yield: 112.4 %

Procedure:
A solution of 3-cyclohexyl-2-methylpyridine (170 mg, 1.0 mmol), in CH2Cl2 (5 mL) was treated with MCPBA (0.33 g, 1.9 mmol) for 18 hours. The solution was then washed with saturated NaHCO3 solution (5 mL), the phases separated, and the aqueous extracted with CH2Cl2 (2×10 mL). The combined organic phases were then dried (Na2SO4), filtered, and concentrated to afford crude 3-cyclohexyl-2-methylpyridine N-oxide as a white solid (0.215 g) which was used immediately in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[Cl-:9].[Al+3].[Cl-].[Cl-].ClCl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:9][C:3]1[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=1[Cl:1]
Reactant: O=Cc1ccc(Cl)s1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(Cl)s1

Procedure:
To a mechanically stirred solution of 31.8 grams (0.217 mole) 5-chloro-2thiophenecarboxaldehyde in 150 ml of methylene chloride, 65 grams (0.487 mole) of anhydrous aluminum chloride was added in small portions. The mixture exothermed and turned purple. To this mixture 20.6 grams (0.29 mole) of chlorine in 250 ml of carbon tetrachloride was added dropwise. The reaction mass was refluxed for about 15 hours, and an additional 15 grams (0.21 mole) of chlorine in 200 ml of carbon tetrachloride was added. The mixture was refluxed for an additional 7 hours. The reaction was quenched by pouring over one liter of ice water. The aqueous layer was extracted with chloroform. The chloroform solution was washed with water and sodium bicarbonate. After drying with anhydrous sodium sulfate and concentration under vacuum, a yellow-brown oil was obtained. The crude 4,5-dichloro-2-thiophenecarboxaldehyde crystallized on standing and was recrystallized from hexane.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([C:20]1[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[C:18]([C:20]4[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OC2CCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OC4CCCC4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclopentyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.592 mmol) described in Manufacturing Example 78-1-4 and 3-ethynyl-pyridin-2,6-diamine (50.3 mg, 0.378 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (206 μL, 1.48 mmol). This reaction mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (64 mg, 31%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(O)cc2)c1)c1ccccc1
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a degassed solution of 1.3 mL DMF at room temperature containing (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (63 mg, 0.22 mmol), 4-iodophenol (121 mg, 0.55 mmol), and triethylamine (0.09 mL, 0.66 mmol) was added dichlorobis(triphenylphosphine)palladium(II) (15 mg, 0.022 mmol) and copper(I) iodide (4 mg, 0.022 mmol). After proceeding for 1 hour the reaction was partitioned between EtOAc and H2O. The mixture was filtered to remove an insoluble brown precipitate and the EtOAc layer was washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown film was chromatographed eluting with CHCl3/EtOAc to give a yellow solid which was recrystallized from CHCl3/hexane to give the title compound as an off-white solid (38 mg, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12](Br)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([OH:21])[C:19]#[CH:20]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:20]#[C:19][CH2:18][OH:21])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(C#CCO)c1
Temperature: 100 °C

Procedure:
A mixture of tert-butoxy-N-[(3-bromo-4-fluorophenyl)methyl]carboxamide (0.6 g, 2.0 mmol, Step A), CuI (38 mg, 0.2 mmol), PdCl2(PPh3)2 (72 mg, 0.1 mmol), propargyl alcohol (0.35 mL, 6.0 mmol) and TEA (12 mL) was heated at 100° C. for 5 h. The resulting mixture was filtered, and the filtrate was concentrated. The residue was purified by SiO2 chromatography to give the title compound. MS (ES+): 297 (M+NH4)+. Calc'd C15H22FN2O3-297.34.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]([OH:15])=O)[CH:8]=[CH:7][CH:6]=2.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.FC(F)(F)OC1C=CC(CN)=CC=1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]([NH:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=1)=[O:15])[CH:8]=[CH:7][CH:6]=2
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(CC(=O)O)cccc2cn1
Agent: NCc1ccc(OC(F)(F)F)cc1
Product: Cc1cc2c(CC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 222B using (3-methyl-5-isoquinolinyl)acetic acid and 4-(trifluoromethyl)benzylamine instead of 5-isoquinolinylacetic acid and 4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 2.77 (s, 3H), 4.12 (s, 2H), 4.37 (d, J 6.1, 2H), 7.47 (d, J 7.8, 2H), 7.68 (d, J 8.1, 2H), 7.86 (t, J 7.4, 1H), 8.03 (d, J 6.4, 1H), 8.36 (m, 2H), 9.03 (t, J 5.8, 1H), 9.77 (s, 1H); Anal. Calcd for C20H17F3N2O+1.85 HCl: C, 56.44; H, 4.57. Found: C, 56.41; H, 4.46.
Reaction SMILES: O=O.Cl.[F:4][C:5]1[CH:6]=[C:7]([S:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]([NH2:24])=[O:23])=[CH:17][CH2:16][CH2:15]3)[CH:8]=[CH:9][CH:10]=1.[H][H]>CO>[F:4][C:5]1[CH:6]=[C:7]([S:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([C:22]([NH2:24])=[O:23])[CH2:17][CH2:16][CH2:15]3)[CH:8]=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: NC(=O)C1=CCCc2cc(Sc3cccc(F)c3)ccc21
Agent: Cl
Agent: O=O
Solvent: CO
Product: NC(=O)[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm) a catalyst solution was prepared in the glass insert of a 6 ml autoclave by reacting a solution of 6.45 mg (0.00668 mmol) of [Ru(trifluoroacetate)2((S)-pTol-MeOBIPHEP)] (S/C 25) in 0.5 ml of methanol with 0.5 ml of methanol containing 0.020 mmol of HCl and stirring for 2 h at room temperature. After addition of 50 mg (0.167 mmol) of 6-(3-Fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acid amide, the asymmetric hydrogenation was run for 18 hours at 40° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was filtered through a silicagel pad and evaporated in vacuo to give (R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide in quantitative yield and with an enantiomeric ratio of 98.8:1.2. The conversion was >=99.9%.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[CH3:47][S:48](Cl)(=[O:50])=[O:49].C(N(CC)CC)C>O1CCCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:42][CH:41]=2)=[N:17]1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 28 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.258 g, 0.43 mmol) in tetrahydrofuran (4.5 mL) was added methanesulfonyl chloride (0.05 mL, 0.64 mmol) and triethylamine (0.30 mL, 2.14 mmol). The final crude product was purified by preparative HPLC (10–100% acetonitrile to H2O, 20 min.) (0.042 g, 28% yield): 1H NMR (CD3OD) δ 7.93 (dd, 1H), 8.54 (br s, 1H), 8.29 (dd, 1H), 8.20 (m, 2H), 7.87 (dd, 1H), 7.62 (m, 2H), 3.23 (s, 3H); ES-MS (m/z) 355 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OCc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 2-chloro-6-methylnicotinic acid (3.0 g), benzyl alcohol (2.27 g), 4-dimethylaminopyridine (2.56 g) in DMF (10 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide (WSC) hydrochloride (4.02 g). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (3.6 g).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:8]=2)=[N:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[N:26]1([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=4)[N:8]=3)=[N:4][CH:3]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: COc1cc(Nc2nccc(-c3ncc(Cl)s3)n2)cc(OC)c1OC
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: COc1cc(Nc2nccc(-c3ncc(N4CCNCC4)s3)n2)cc(OC)c1OC
Temperature: 100 °C
Yield: 23.6 %

Procedure:
To solution of [4-(5-Chloro-thiazol-2-yl)-pyrimidin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (150 mg) in dimethylsulfoxide (2 ml) was added piperazine (300 mg). The mixture was heated to 100° C. for 5 hours then allowed to cool and concentrated under high vacuum to an oil. The residue was purified by HPLC with 0.1% TFA/water acetonitrile as eluant to afford the sub-titled compound as an yellow solid (40 mg, 25%); IR (solid) 1567, 1504, 1432, 1411 cm−1; 1H NMR (400 Mhz, CDCl3) δ 1.3-1.5 (1H, br s), 3.1 (4H, s), 3.25 (4H, s), 3.85 (3H, s), 3.95 (6H, s), 7.05 (1H, s), 7.15 (1H, s), 7.19 (1H, s), 7.40 (1H, m), 8.6 (1H, d); MS (ES+) 429.3 (M+1), (ES−) 427.3 (M−1).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12

Procedure:
Reagents: Isatoic anhydride (6.13 mmols, 1 g); Sodium hydride (9.2 mmols, 0.22 g); Benzyl bromide (12.3 mmols, 1.4 g). Yield: 0.2 g (15%), white solid, m.p.=139° C.-140° C.
Reaction SMILES: C(OP([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.[CH2:23]([O:25][C:26]([N:28]1[CH2:32][CH2:31][C:30](=O)[CH:29]1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:27])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26]([N:28]1[CH2:32][CH:31]=[C:30]([CH2:9][P:10]([O:12][CH2:13][CH3:14])([O:15][CH2:16][CH3:17])=[O:11])[CH:29]1[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:27])[CH3:24]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)C1C(=O)CCN1C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1C(CP(=O)(OCC)OCC)=CCN1C(=O)OCC
Temperature: 25 °C

Procedure:
A stirred solution of 5.3 ml of bis-(diethylphosphono)methane in 30 ml of anhydrous tetrahydrofuran (THF) under nitrogen is cooled to -78° and 8.5 ml of 2.5M butyl lithium is added dropwise. After stirring 5 minutes a solution of 4.64 g of ethyl 1-ethoxycarbonyl-3-oxopyrrolidine-2-carboxylate [J. Am. Chem. Soc. 86, 5297 (1964)]in 30 ml dry THF is added dropwise rapidly. The solution is heated at reflux for 18 hours, cooled to room temperature and concentrated; 40 ml of 1N hydrochloric acid is added and the mixture is extracted with 100 ml of methylene chloride. The organic fraction is washed with 25 ml water, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography using ethyl acetate as solvent yields ethyl 1-ethoxycarbonyl-3-(diethylphosphono- methyl)-2,5-dihydropyrrole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.[CH3:19][C:20](Cl)=[O:21].Cl>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:20]([O:12][CH2:11][CH:10]=[CH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:21])[CH3:19]
Reactant: CC(=O)Cl
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC=Cc1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Yield: 96.8 %

Procedure:
Treat a solution of the product of step 2 (13.2 g, 65 mmol) in CH2Cl2 (250 mL) at 0° C. with pyridine (7.89 mL, 97.5 mmol, 1.5 eq) and dimethylaminopyridine (397 mg, 3.25 0.05 eq), followed by CH3COCl (6.48 mL, 74.75 mmol, 1.1 5 eq). Allow the mixture to warm to 23° C., pour into 1M HCl (100 mL) and wash the resulting organic layer again with 1M HCl (100 mL), followed by water (5×100 mL; pH=6.5-7). Dry the organic layer (Na2SO4) and concentrate to obtain 15.4 g (62.9 mmol, 97%) of 3-(3,4-dichlorophenyl)-2-propene-1-ol acetate as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH2:15]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[CH2:16][CH3:17]>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:21]1[CH2:22][CH2:23][N:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH:20]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Reactant: CCCN1CCC(=O)CC1
Product: CCCN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 88.7 %

Procedure:
Beginning with 1.50 gm (7.1 mMol) 5-methanesulfonylamino-1H-indole and 1.4 mL (9.3 mMol) 1-propyl-4-piperidone, 2.1 gm (88.2%) of the title compound were recovered as a yellow powder.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][NH2:14]>O1CCCC1.CO>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:14][CH3:13])=[O:3]
Reactant: CN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1N
Yield: 97.8 %

Procedure:
Isatoic anhydride (10 g, 61.3 mmol) was suspended in tetrahydrofuran (200 ml) and treated dropwise with methylamine in methanol (40%, 10 mL) with stirring. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure to afford the product 2-amino-N-methylbenzamide (9 g, yield 97.8%). 1H NMR (400 MHz, CDCl3) δ ppm 7.14-7.32 (m, 2H), 6.60-6.72 (m, 2H), 6.05 (br s, 1H), 2.97 (d, 3H, J=5.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>C1COCC1.CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[CH:26][CH:27]=1
Reactant: Cc1nnnn1C
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1CC(O)(c1ccccc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A solution of 1,5-dimethyltetrazole (29.25 g; 0.298 mole) in dry THF (400 mL) was cooled to -78° C. and treated with n-butyllithium (133 mL of a 2.5M solution in hexane; 0.3325 mole) over 30 minutes. The mixture was stirred at -78° C. for 30 minutes and treated with 4-fluorobenzophenone (50 g; 0.25 mole). The mixture was stirred at -78° C. for 30 minutes and allowed to warm up to 23° C. over 2 hours. The reaction was quenched with 2N HCl (100 mL) and the organic solvent was removed by evaporation. The residue was extracted with CHCl3 (2×100 mL) and the combined organic layers were dried (Na2SO4) and evaporated to afford a brown oil. Purification by chromatography using 20% EtOAc-hexane as eluent afforded the title compound as a white solid (46.3 g; 62%). m.p.=113°-114° C. (crystallized from EtOAc-hexane). MS (CI): m/e=299 for (M+H)+ ;
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].[CH2:36](Br)[CH:37]=[CH2:38].O>CN(C=O)C>[CH2:38]([N:20]([C:19]1[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:3])=[O:2])[C:15]=2[N:16]=[CH:17][N:18]=1)[C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of (R)-tert-butyl 3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1.0 g, 2.1 mmol) in DMF (5 mL), NaH (60% suspension in mineral oil, 100 mg, 2.5 mmol) was added at 0° C. and the reaction mixture was stirred for 1 h. To the reaction mixture was added allyl bromide (308 mg, 2.12 mmol) and the reaction mixture was stirred for 6 h. The solution was diluted with ice-cooled water and stirred for 15 min, the solution was then extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the crude product that was purified by column chromatography (silica gel, gradient, EtOAc in hexanes) to give (0.9 g, 83%) of the titled compound. 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.43 (d, J=3.2 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 6.57 (d, J=3.2 Hz, 1H), 5.98-5.90 (m, 1H), 5.26-5.19 (m, 2H), 4.62-4.51 (m, 1H), 4.29-4.09 (m, 4H), 2.85 (t, J=11.6 Hz, 1H), 2.68-2.60 (m, 1H), 2.41 (s, 3H), 1.97-1.93 (m, 1H), 1.83-1.72 (m, 2H), 1.65-1.58 (m, 1H), 1.42 (s, 9H). LCMS [M+1]: 512.